Hexane- Methanol Liquid-Liquid Extraction as a Separation Technique

This idea is speculative. As far as I know, there is as yet no experimental evidence to support it. For example, it is not known for any particular reaction mixture how much of that mixture could be mixed with how much of the hexane-methanol azeotrope and still actually get the essential separation into the two phases. Also, even if liquid layer separation is achieved, we cannot know in advance what the difference in partition coefficients between mixture constituents will be even though this will determine how practical the separation will be and how many times the procedure would need to be repeated to get a useful concentration of even one species.

The azeotropic mixture of hexane and methanol splits into two phases when cooled below 35 C. At temperatures below the UCST there exist two phases containing different proportions of hexane and methanol. The azeotrope between hexane and methanol has bp 50 C; its composition is 73.1% hexane and 23.9% methanol. The relative volumes of the upper and lower phases are 67.8: 32.2, about two parts to one part. When the hexane-methanol separates on cooling the composition of the upper layer will be 85% hexane and 15% methanol with a specific gravity of 0.675. The composition of the lower layer will be 42% hexane and 58% methanol with a specific gravity of 0.724.

 

A mixture of substrates (such as the untreated components of a reaction mixture)  as evaporated to an oil or oily solid could be mixed with the warm single phase above 35 C, then cooled to split into two phases into which the mixture of substrates would partition. Subsequently, cutting the phases and evaporating each would give two new compositions with a different ratio of the substrates from each of the two hexane-methanol mixtures.

These substrate concentrates could then each separately again be dissolved in a new portion of the single phase azeotropic above the 35 C UCST and again cooled and the phases separated and evaporated. These oily residues are treated just the way solutions are treated in a liquid-liquid extraction to improve the degree of separation of the substrates.

The disadvantage of the methodology will be that each time the extracts need to be evaporated essentially to dryness because otherwise the proportions of liquids hexane and methanol will change so that the two phases will not continue to separate.

The advantage is that because both phases contain the same two solvents-just in different proportions, the partitioning of substrates between the phases might be expected to be closer to 1:1 and so the selectivity in the partitioning of two similar substrates might be more sensitive. That is to say, one substrate might be slightly more soluble in the methanol-rich phase while the other might be more soluble in the hexane-rich one. 

If no separation of liquid phases occurs at any stage it is possible that a larger proportion of the hot azeotropic hexane/methanol mixture is required. This is easily rectified. Simply add more of the hot azeotrope composition and rewarm the total solution until above the UCST and recool.

Using Dissociative Extraction to Separate Ketones

 This article is 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. 

Glacial Acetic Acid and Cyclohexane May be an Extraordinary Useful Solvent Combination

 The combination of glacial acetic acid and cyclohexane seems like an extraordinarily flexible reaction solvent system as outlined below. Its use for a variety of reaction types should be explored.

Acetic acid and cyclohexane are two very different substances that are nevertheless miscible above 3.9℃ (their UCST). In a cooled reactor, these will form two separate liquid layers allowing for liquid-liquid partitioning of any solutes therein. More easily than in the laboratory, in the plant the reactor can be kept closed and inerted; consequently, more easily water-free. The acetic acid in the lower layer will be glacial acetic acid so long as water is neither introduced into nor produced in the procedure. More polar components of a reaction conducted therein might be removed by simple phase separation. Glacial acetic acid will be much better at dissolving some substances than a mixture with water present to any extent.

After a cut, there will still be some acetic acid residue in the cyclohexane layer, but acetic acid and cyclohexane give an azeotrope bp. 79.6 ℃ that contains 2% acetic acid. Thus, the predominantly cyclohexane layer can be freed of even traces of acetic acid by distilling out from the reaction vessel a small first fraction. A work-up is possible, still without adding any water!

Where Could Such a Solvent System Be Useful?

This cyclohexane/glacial acetic acid solvent mixture, above 3.9℃ when it is a single-phase, might be a good candidate for conducting acetylations with either acetic anhydride or acetyl chloride reagents. The excess reagent might be removed without decomposing it by cooling to <0℃ and cutting the two phases.

This mixture of fluids might also serve for dehydrations or acid-catalyzed rearrangements. Adding anhydrous hydrogen halides would protonate acetic acid, giving rise to a very strong acid in situ. Excess hydrogen halide would be removed with the acetic acid-rich layer when the reactor was cooled. The system would protonate olefins perhaps inducing rearrangement but hydrogen halide would be unlikely to add across the unsaturation since the halide anion would be strongly solvated and deactivated by hydrogen bonds with the acetic acid.

Acetic acid might catalyze enol formation from ketones. Enols could react internally with a terminal double bone to give a cyclic product or they could be condensed, dehydrated, and so dimerized.

This post is speculative. It does not report experimental evidence.  

Using a Gas-Expanded Solvent for Recrystallizationto Make Possible a Second Crop of Crystals

 The proposed method for obtaining multiple crops of crystals from a gas-expanded solvent recrystallization needs to be demonstrated in the laboratory.

One of the advantages of performing crystallization of a substrate from a single solvent by cooling as opposed to causing crystallization by diluting a first solvent with a miscible anti-solvent is that one can try for a second crop simply by reducing the volume of the filtrate, recool the reduced volume to yield more solid. One can do this because the solvent composition isn't being modified. This advantage would be retained if the crystallizing solvent is a lower-boiling binary azeotrope.

In the alternative, where an anti-solvent is being mixed in to create the required supersaturation considerable tedious work is required to remove all the anti-solvent and concentrate that first pure solvent before a second crop can be attempted.

But if the anti-solvent is a gas under plant conditions, this re-establishment of a single solvent and its concentration is simple. Take for example a mixed-solvent recrystallization that was originally being performed by dissolving the substrate in toluene and then decreasing the overall solubility by adding hexane and then cooling. Suppose instead one dissolves the substrate in toluene cools the solution but instead now bubbles in butane gas. The butane will dissolve in the toluene but the solubility of the substrate will decline in just the same fashion that occurs by adding hexane. The product will crystallize. You cannot filter using a vacuum since this would drive off the butane. Filtration must instead be done by pushing the slurry through the filter cloth with pressure. When the crystallized substrate has been caught on a filter, evacuating the system will easily remove the butane from the filtrate leaving the toluene which can be further concentrated. A second crop can be isolated by repeating the gas expansion with butane.

Furthermore, although mixed solvents are not normally recycled and reused in multi-purpose fine chemical plants, Gas-expanded liquids are an exception since simple distillation rather than fractional distillation is sufficient to do the job.

Any mixed solvent recrystallization that uses cyclohexane, hexane, heptane or petroleum ether can be rejigged as a gas-expanded liquid mixed solvent recrystallization using butane thereby enabling taking a second crop of crystals to raise the yield.

Unusual Solvent Immiscibilities

 In a chemical process step, the unseparated mixture of positional isomers of xylene is cheap enough to serve as either a reaction solvent or solvent for use in purification.

I am always on the lookout for pairs of organic solvents that can serve as immiscible phases for solute partitioning by liquid-liquid extraction since this is a very robust, simple, and scalable purification method.

It is reported on-line that xylene and trichloroethylene are immiscible. This would be very surprising and the partitioning of different solutes between these two would be very interesting and possibly useful practically. This could be an easy undergraduate investigation that could be reported as a comment on the Kilomentor blog.

Although toluene is immiscible with wet DMSO, it is miscible when thoroughly dried. However, the commercial xylene mixture is reported to be immiscible with even dry DMSO. This mixture of positional isomers also is reported to give two liquid phases with dimethylformamide and trichloroethylene. The extra saturated carbon apparently makes the difference. 

Of the three combinations:

xylenes/DMSO

xylenes/DMF

xylenes/ trichloroethylene

the final one seems the most remarkable.  I would appreciate it if someone who is actually in a lab (I am retired) would either confirm or disavow it in the comment section. It would be very interesting to see how different compounds are partitioned between these two.

What third solvent will break the miscibility between THF and Water?

 Tetrahydrofuran and water when mixed together form a single-phase whatever their relative proportions. Diethyl ether, which has two more hydrogens per molecule, forms two distinct phases when mixed with water. 2-Methyltetrahydrofuran forms two layers as well. Methyl ethyl ketone with the same molecular formula forms two layers. 

Among four carbon alcohols, 1-butanol is only soluble between 6 and 9% by weight at 25℃. 2-Butanol is only soluble about 18% by weight at 25℃. 2-Methylpropanol is only soluble about  7-8% by weight at 25℃.

Therefore, each of these can be called immiscible with water; however, t-butanol with the same molecular formula is completely miscible with water.

Clearly at four carbons and one oxygen in a molecular formula we are getting close to some discontinuity in mixtures with water.

This is more than just curious. It is important because reactions conducted in these solvents are often quenched and worked up by adding water and it makes a difference whether they form one or two separate fluid layers.

The situation with regard to THF is particularly important because organolithium and Grignard reagents are so often necessarily or most often prepared in this solvent. 

It is of considerable consequence that THF does not provide any azeotrope that can be used to dry THF.

A mixture of 18 grams of water and 64 grams of THF would contain 1 mole of each molecule. Here is my question: What is the smallest weight of any other common solvent that, added to this mixture, would give a clean interface between two distinct layers, and what is that third solvent?  I do not have the answer. But the answer has a practical importance because such an addition would provide one simple element of a work-up for a reaction conducted in THF and quenched with water.

For simplicity and to inspire imaginative thinking I have chosen the moles of water and THF to be 1:1. My guess would be 2-methyl propanol.  It is apparently poorly solvated by water alone but it would provide a hydrogen bond to donate to the electron pairs of THF. Another promising candidate would be t-butanol. If t-butanol caused separation into two discrete phases it would be truly remarkable since all three solvents are miscible as binary pairs! However, the hydrogen-bonded complex between a t-butanol molecule and a THF molecule might mutually satisfy their polarity needs and present a hydrophobic exterior to the water.

If I had a third guess, I would add a carbon and try 1-methyl-2-butanol (t-amyl alcohol). That would preserve the same hydrogen bonding but increase the overall hydrophobicity of any binary complex. t-Amyl alcohol has only an 11% solubility in water at 25℃.

I wish someone would do this last experiment:18 grams of water, 64 grams of THF, then add slowly t-amyl alcohol with stirring until 78 grams of the alcohol were added. Do the layers separate?

Constant Boiling Binary Azeotropes as Reaction Solvent Systems

 None of the particular identified solvent systems have been tested as reaction solvents.

Constant boiling azeotropes are potential solvent systems for reactions.  Compared to any random solvent mixture, their advantage is that the composition can be consistently prepared with a stable ratio of components so long as the pressure can be held constant.  The mixture can be repurified at the end of its use, so long as the other components of the waste reaction mixture are not volatile, simply by distilling the residual solvent mixture.

Azeotropes are typically mixtures of quite unlike solvents so the combinations might be expected to show,  in most instances, substantially different properties from any pure liquid solvent.

What might some of these particularly attractive candidates be?

Acetic acid (58.5)          Chlorobenzene (41.5)   bp 114.7

Acetic acid (38.5)             Tetrachloroethylene (61.5)   bp 107.4

Acetone (88.5)  Carbon Tetrachloride (11.5)   bp 56.1

Carbon Disulfide (63.0) Ethyl formate (37.0)          bp 39.4

Cyclohexane (72.0)         Nitromethane (28.0)          bp 70.2

Dibutylamine (49.5)         Water (50.5)           bp.97.0

Acetic acid/ chlorobenzene and acetic acid/tetrachloroethylene could be interesting solvents for free-radical reactions. both would also be more polar versions of chlorobenzene or tetrachloroethylene that would easily send all their organic solutes into the halogenated layer by simply adding water to the completed reaction mixture.

Acetone/carbon tetrachloride would be a less polar, lower dielectric constant version of acetone or methyl ethyl ketone.

Carbon disulfide/ethyl formate might turn out to be a more convenient fluid for working with compounds particularly soluble in carbon disulfide.

Cyclohexane/nitromethane probably has an upper critical solution temperature within a practically useful range. I the mixture can be cooled to give two separate phases this may be useful in separations.

The dibutyl amine/ water mixture will very likely be useful for dissolving more hydrophobic solutes into an aqueous phase.

It is frequently argued that single component solvents are to be preferred over solvent mixtures because they are:

(1) easier to purify for reuse, and

(2) easier to acquire in precise, and pure form.

The first of objections is usually a 'red herring' as far as pharmaceutical or fine chemical synthesis is concerned. Solvents used to prepare such products are exceedingly rarely purified for reuse. The reason is simple; the analyses required to demonstrate that the recycled material is equivalent to fresh solvent are too costly and time-consuming.

The supposed second disadvantage simply would not be true for a lower boiling binary solvent azeotrope.