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.

 

A Speculation concerning How to more easily Work-Up Reactions with High Boiling Glymes as Solvent

THIS IS A SPECULATION that is why it can be a subject for undergraduate or graduate study.

The glymes are methyl ethers of polyethylene oxide. They aren’t particularly popular solvents for organic synthesis because they are high boiling and therefore difficult to remove from reaction products. Also because they are quite soluble both in organic solvents and water they cannot so easily be removed by liquid-liquid partitioning. The speculation is whether it might be removable by solid-liquid partitioning!  

Urea is a solid below its melting point of 153℃. But urea will dissolve in hot methanol and glyme molecules of greater length than 8 atoms crystallize as inclusion complexes with urea from methanol. So adding a hot solution or slurry of urea in methanol into a reaction mixture in which a glyme had been the solvent might be expected to crystallize out the glyme-urea inclusion complex leaving the rest of the reaction mixture dissolved in methanol containing some residual urea.

For most organic chemical reactions a homogeneous liquid medium ( a solvent) is used to efficiently bring reaction partners into contact under conditions compatible with their reaction together. Generally, reaction occurs more smoothly and completely if all reactants, reagents, and processing chemicals dissolve in the liquid medium. Since a medium’s physical properties determine what it can dissolve perhaps a mixture of materials might be able to dissolve a wider range of substances. The downside is using a complex solvent system.

Suppose the solvent mixture separated itself? Urea dissolves in methanol. Tetraglyme, which is a liquid linear polyether, forms complexes with urea. In excess methanol, it can perhaps be expected that the straight-chain tetraglyme might fill the channels within the crystalline urea so that it crystallizes as the bulk methanol cooled. Filtering might leave in the filtrate only some residual urea and a methanol solution of whatever remains from the reaction mixture that is soluble in methanol alone. What is unknown is  (i) how complete is the precipitation of tetraglyme with crystallizing urea in methanol (ii) is the volume of urea-methanol needed to crystallize tetraglyme practical (iii) whether the components that it is hoped will involve themselves in reacting together interfere with the inclusion complex formation and (iv) whether they might interfere in the complete crystallization of the urea inclusion complex.

Certainly, when hot, methanol, urea, and tetraglyme together should be a good environment for dissolving a wide range of different reagents and substrates. Methanol would provide hard acid protons and hard base oxygen, urea would provide soft base electron pairs from nitrogen and oxygen and tetraglyme could present a multidentate ligand to wrap around any metal ions.

The methodology could also be used to work-up reactions done in tetraglyme alone. Certainly, there are many reaction types that could benefit from tetraglyme as solvent. The urea and methanol could in these cases be added to free the reaction mixture of tetraglyme. Finally, after removing insoluble urea-tetraglyme inclusion complex the residual liquid medium could be diluted with water and extracted with a cheap immiscible organic solvent to extract away key reaction products. 

Separating Sulphur-containing from Sulphur-free Compounds both in the Lab and At Scale

Long ago, In 1964, G.M.Badger, N. Kowanko and W.H. F. Sasse submitted a short communication  to J. Chromatog. 13, (1964) 234 titled, Chromatography on a column of Raney cobalt.The small experimental read as follows:

“The freshly prepared Raney cobalt (ca 7.5 g) was mixed with clean sand and packed into a chromatographic column (1.2 cm X 10 cm.). A mixture of isoeugenol (0.5 g) and 2,5-dimethylthiophene (0.5 g) was applied to the column and eluted with methanol ( a 3-ft head of liquid was required). Evaporation of the first fraction 930 ml) gave sulfur-free isoeugenol (0.477 g). Subsequent fractions contained only trace amounts of isoeugenol and were also sulfur-free. The dimethylthiophene was subsequently recovered by Soxhlet extraction of the cobalt-containing solid with methanol.” (my italics).

The discussion pointed out that active cobalt metal binds sulfur containing compounds by chemisorption; however, unlike Raney nickel, Raney cobalt has a much reduced tendency to desulfurize. Nevertheless, this binding is powerful, much stronger than simple adsorption, as the rigorous conditions described for removing the dimethylthiophene from the solid phase attested.

What this suggested to me was that the method would not need to be conducted as a column chromatography. It would probably work simply by stirring the solid with a solution containing the sulfurous material, passing through filter aid, and washing. Thus, the method could separate sulfur- containing from sulfur-free materials by filtration as easily as an insoluble polymer is separated from a solution.

That  desulfurization under the conditions of a separation is unlikely is further suggested by another paper [1960] by the same authors which contains the sentence “Desulphurisation with Raney cobalt was similar to that with W7-J Raney nickel in that, although little reaction occurred in boiling methanol, it was complete in diethyl phthalate at 220.”

It would seem that, besides obviously being able to separate the sulfur containing from sulfur free compounds, the technology should be adaptable to separate compounds that have been derivatized with a sulfur a containing reagent from compounds without such an appendage.

It might be that the method of recovery of the chemisorbed compound could be improved. Eluting with a solvent containing carbon disulfide or COS might speed the recovery without ireversibly contaminating the eluting solvent.

Also, a chemisorbant simpler to prepare than Raney cobalt might be available by reducing a cobalt salt with sodium borohydride to give a Cobalt boride analogous to the Nickel boride catalysts called P-1 and P-2 developed by H. C.Brown et al. 

Can the Diisopropyl ether (DIPE) –Water Azeotrope be used to Dry Dipolar Aprotic Solvents like DMSO?

 

Reactions performed in dipolar aprotic solvents such as N-methylpyrollidone, dimethyl formamide, N-methyl formamide, dimethylacetamide, or dimethyl sulfoxide are often drowned out with water and then extracted to isolate organic products.  No cheap and convenient method has been worked out to separate these polar organics from the bulk of the water and return the dipolar aprotic to an anhydrous condition suitable for reuse.

On the basis of the physical properties of the chemicals, the following might be workable but KiloMentor has seen no experimental work to substantiate it. 

KiloMentor has argued that diisopropyl ether can safely be used at scale because better precautions and practices are taken than in the laboratory. Diisopropyl ether (DIPE) forms an azeotrope with water that is reported to boil at 62.2 C. This is a heteroazeotrope.  That means that the vapour is in equilibrium with two immiscible liquid phases. According to the Chemical Rubber Handbook, DIPE and water form an azeotrope that on condensation splits into a water-poor DIPE upper phase and a water-rich lower phase. Addition of DIPE, therefore, to one of these higher boiling solvents and water, and boiling of the ternary mixture under a Dean-Stark trap with the continuous return of the top DIPE phase might realistically gradually separate a lower water-rich phase which could be periodically drained away. The high-boiling solvent that is being dried would theoretically be confined to the still pot.

In the real-life situation, however, a small amount of the high-boiling solvent could co-distill. Enough of this vapour, entrained in the reflux stream, could scupper the procedure by making the distillate a single phase, so this idea would need to be thoroughly tested for each different dipolar aprotic solvent. Nevertheless, if it works and your facility has unused distillation capacity, solvent recovery could be profitably practiced.

 It is crucial for a practical process that the DIPE be recycled since the distillate is 97% DIPE and only 3% water. Recycling is essential to be able to remove a large amount of water using only a small amount of DIPE.

Other solvents that boil above 100 C that can potentially be separated from water and dried using DIPE are nitromethane, acetic acid, dioxane, ethylenediamine, sulfolane, and isoamyl alcohol.

After the water has been completely removed continued distillation will drive over the DIPE itself. Even if small amounts of DIPE remained in the recovered dipolar aprotic solvent they are usually unreactive. Of particular importance, they are inert towards organometallic reagents.

For safety remember that DIPE needs to be worked with under inert gas to prevent the accumulation of explosive peroxides. The solvent very readily forms peroxides but fortunately, plant processing is invariably done under inert gas.