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.

Persilylation to Provide a Mixture Separable by Liquid-Liquid Extraction

 The KiloMentor blog emphasizes the usefulness of simple, robust, scalable methods for work-ups and isolations in organic chemical process development.

Biphasic organic solvent systems such as methanol/hexane can in principle be very useful for the simple extractive separation of components of a reaction mixture. The trick for success is to get partition ratios that are neither too small (<0.2) or too large (>5).

The idea being explored in this blog is whether persilylation of a mixture of solutes from a completed reaction could give a modified mixture that could be separated by liquid-liquid extraction between two immiscible aprotic solvents.

While it is true that most biphasic organic solvent systems comprise a protic component and such a solvent would use up all the silylating agent and prevent silylation, there are aprotic solvents that can be mixed and retain two liquid phases. Cyclohexane forms two liquid phases with any one of acetonitrile, propionitrile, nitromethane, nitropropane, dimethylsulfoxide, dimethylformamide or dimethylacetamide. Hexane and heptane would likely behave similar to cyclohexane.  Sulfolane and t-butyl methyl ether which are both aprotic and are only partially miscible. 

KiloMentor proposes that silylation of all the components of a mixture to be separated should decrease or leave unaltered their polarities and perhaps cause their partitioning between the component phases of a two-phase solvent pair to become more competitive. Smaller partition ratios could make a couple of stages of counter-current extraction feasible for a separation.

Disclaimer

Please be warned that this methodology has not been experimentally verified in any situation that I know about.  What I can say is it is simple enough to work and I cannot see any particular difficulty.

I have always urged my coworkers to make a clear distinction between facts and theory and this is my effort to do the same.

Making the Silylation Facile

To proceed in this way, a practical method to persilylate all the functional groups in all the components in a reaction mixture A necessary capability is is required. A practical consideration is that the silylation procedure must be inexpensive; otherwise, the additional reagent cost will make the procedure uncompetitive with alternatives.  Fortunately, it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for effectively all functional groups.  Although this has been in the literature for many years, it is infrequently used and seems to have today vanished from our chemical toolboxes.

Cornelis A. Bruynes and Theodorus K. Jurriens, then scientists at Gist-Brocades in Delft Netherlands, published a paper called Catalysts for Silylations with 1,1,1,3,3,3-hexamethyldisilazane in J. Org. Chem. 47, 3966-3969 1982.  They reported that the following compound types could be trimethylsilylated using the title reagent and an appropriate one of their catalysts with yields of typically more than 90%:

Alcohols, phenols, carboxylic acids, hydroxamic acids, carboxylic amides, and thioamides, sulfonamides, phosphoric amides, mono and dialkyl phosphates, mercaptans, hydrazines, amines, NH groups in heterocyclic rings, and enolizable β-diketones

The silylation times were in all cases no more than two hours and the catalyst concentration is typically from 0.001-10.0 mole percent.

Catalyst Structures

Although many catalysts are claimed (there is a corresponding patent  EP81200771.4 now expired), five were used in the most examples:

• Saccharin [81-07-2]
• Sodium saccharin [128-44-9]
• Bis(4-nitrophenyl)N-(4-toluenesulfonyl)phosphoramidate [81589-21-`]
• Tetraphenylimidodiphasphate [3848-53-1]
• Bis-(4-nitrophenyl)N-trichloroacetyl)phosphoramidate [38187-67-6]

The registry numbers for these catalysts are given in square brackets.

Methods of Application of this Idea

There are two variants of this idea. In one, all the solutes in a reaction mixture are persilylated and allowed to partition between the two immiscible solvents. In the second all the solutes in a reaction mixture are mixed with the two immiscible solvents and the silyating reagents are added and the mixture is analyzed as the competitive silylations proceed and the partitioning of unsilylated, partially silylated, and completely silylated materials accumulate in the two different phases. This second is a kinetic silylation with simultaneous partitioning. 

To use this either strategy all that ought to be necessary would be to

• make a solvent change into acetonitrile, propionitrile, dimethylacetamide, dimethylformamide, nitromethane or nitroethane whichever is appropriate for the separation trial
• add the minimum necessary amount of a catalyst
• add the calculated amount of hexamethyldisilazane
• heat for the requisite time to get a complete or other requisite degree of silylation of the mixture with the expulsion of the co-product ammonia
• adjust the solvent volumes so that the biphasic mixture will be produced at the appropriate temperature
• cool to that temperature if necessary
• separate the phases
• repeat extraction if necessary
• hydrolyze the silyl derivatives and recover the products from their respective phases

Potential Problems

It will only be determined by actual experiment with a particular mixture of solutes to determine how high a relative concentration of the solutes can be worked with before the biphasic solvent mixture goes homogeneous. Obviously, there is some point where the concentration of the solutes will wreck the balance of solvent properties that allows the two phases to coexist

As is always the case if one adds something to promote a separation that facilitating agent must itself be separated in the end. So it is with the catalyst, which must remain in one or the other phase along with some elements of the mixture being separated.

Consider the possibility of partitioning a reaction mixture between two of these partially immiscible solvents and then with mild stirring adding a silylation catalyst followed by an insufficient amount of a silylating agent such as hexamethyldisilazane.

What would happen?

I would think that whichever solute silylates faster will be partitioned into the less polar hydrocarbon layer where it would be protected from further reaction. The reagent trimethylsilyldiethylamine is probably the most statically demanding silylating agent one could try to get kinetically controlled silylation.

Extractive Crystallization-The Use of Methyl or Ethyl Salicylate to Crystallize Solutes Insoluble in both Hydrocarbon Liquids and Water

 The following is a research idea. As far as KiloMentor is aware It has not been demonstrated. Before any trials, an up-to-date literature search is recommended.

A very large number of organic compounds are essentially insoluble in both pure hydrocarbon solvents and in water. As such they would be expected to also be insoluble in a two-phase mixture of water and hydrocarbon. Solutes that belong to this large group would be candidates for a crystallization/recrystallization procedure that, as far as I know, has not been tried to date.

Methyl  and ethyl salicylates are very low melting solids and high boiling liquids: methyl salicylate mp -8.6 C; Bp 220-224 C; ethyl salicylate mp 1 C; Bp 232.5 C.

They share another common property. When stirred with aqueous alkali they are hydrolyzed to 2-hydroxybenzoate salts. What is less commonly recognized is that the presence of a separate hydrocarbon phase would not effectively inhibit this hydrolysis. The reason: the free phenolic substituent essentially drags the ester into the aqueous phase where the base attacks the ester functionality irreversibly after which it no longer has any affinity for the hydrocarbon layer. 

Unlike hydrocarbons or water, these compounds will be good solvents for a wide variety of other organic materials. They can interact using Van der Waal dispersion forces, dipole-dipole interactions, and hydrogen bonding using both the phenolic hydrogen bond donor and the ester carbonyl hydrogen bond acceptor. Furthermore, these compounds are not particularly expensive and are readily available at industrial scale. They have been demonstrated to be safe. Methyl and ethyl salicylates are flavoring and perfume chemicals. 

 
Suppose we choose to dissolve a solute of interest in a combination of a highly apolar poor solvent, like the hydrocarbon heptane for example, and as solubilizing agent methyl or ethyl salicylate. Such a combination will have the property of having a boiling point at least as high as the hydrocarbon used but will have the enhanced dissolving power provided by the additive. When the mixture is all a single solution it is cooled to ambient temperature and an immiscible aqueous solution of base is added. Even with only very weak stirring hydrolysis in the two-phase medium will result in the salicylate being taken into the aqueous phase. Now with its solubilizer degraded neither hydrocarbon nor aqueous phases will have appreciable solubility for the substrate so it should slowly crystallize out.

The mechanism by which the methyl or ethyl salicylate gets hydrolyzed and retained in the aqueous phase as carboxylate salt is the same extractive hydrolysis that was featured in another KiloMentor blog.

Wide Range of Acceptable Solutes

Even solutes containing functional groups sensitive to aqueous alkali can be expected to safely undergo this treatment. Molecules without active hydrogens (such as phenols, carboxylic acids) will not be extracted out of the hydrocarbon phase and so will be protected from significant alkaline hydrolysis.

Hypothetical Examples

An example of a preparation that might be improved using this methodology can be found in Organic Synthesis Col. Vol. 1 pg. 60 Anthrone Synthesis. The anthrone is finally crystallized from 3:1 benzene and petroleum ether. It is reported that about 12 g of the 3:1 mixture is required for each gram of anthrone.  The yield percent recovery is 62/82.5. An effort is made in this preparation to recycle mother liquors and this reuses about 2/3 of the liquid. The anthrone is much more soluble in benzene than in the petroleum ether antisolvent.  It would be interesting to see how the purification would proceed with heptanes as antisolvent and one of these hydroxyl benzoate esters as the solvent  with dissolution at the reflux temperature of heptanes.

Another opportunity to use this technology seems to be presented by the bromination of anthracene to 9, 10-dibromo anthracene. A process is described in Organic Synthesis Col. Vol. 1 pg. 207. This procedure uses carbon tetrachloride as solvent. This would be unacceptable in scale-up to-day since carbon tetrachloride is a recognized carcinogen.  It might work to brominates anthracene with bromine in heptanes. The dibrominated product is likely to be poorly soluble in heptanes and anthracene itself would only be somewhat better. In the heated reaction mixture, the anthracene would probably dissolve enough to allow the reaction to proceed. At the end, the crude dibromoanthracene would be precipitating. To recrystallize and recover the solvent one of our salicylates could be added with heating to get a solution; the combination then filtered hot; dilute aqueous alkaline to hydrolyze and extract  the hydroxyl benzoate ester. Since the 9, 10-dibromoanthracene would then become insoluble both in the aqueous and the hydrocarbon phases it would crystallize.

Other Possible applications

Other compounds from Organic Synthesis that could benefit from purification from a two-phase mixture of aq. alkali and high boiling hydrocarbon solvent: desoxybenzoin pg. 156: desyl chloride pg. 159; dibenzalacetone pg. 167; ethyl 2,3-dibromo-3-phenylpropionate pg. 270; m-nitroacetophenone pg. 434; Organic Synthesis Col. Vol. III acenaphthenequinone pg. 1; acenaphthenol-7 pg. 3;  

Tannic Acid as a Promising Hydrotrope For Separation and Purification of High-Value Products

Most hydrotropes are made by dissolving organic salts at a concentration of at least 1M in water. Covalently bonded materials do exist that form hydrotropes. The best known is urea. Another inexpensive, non-ionic organic material that is highly soluble in water and that can be expected to promote the dissolution of other organic substances is tannic acid.     
                 
Molecular Formula - C₇₆H₅₂O₄₆
Molecular Weight - 1700
Melting point - 218°C
Water solubility - 1g/ 0.35 ml

Speaking roughly to produce a hydrotrope a chemical must dissolve in water to give a 1M solution. A 1M solution of tannic acid would contain 1700g of organic solid per liter of water. That would be 1.7 gm per milliliter. The solubility of tannic acid in water is 4.88 gm per milliliter. One could achieve a solubility of 2.87M if required in a saturated solution. Tannic acid is a material available in industrial quantities at a practical price. Sigma-Aldrich sells 500 grams for less than $100.00. Considering that only 60 g of urea are needed to produce a 1M aqueous solution that would give an effective hydrotrope and supposing that we provide three times as much tannic acid by weight, that would just be 180 g per liter that would not cost more than $75.00!

The molecule shown in the figure is only one representative (perhaps the major one) of the constituents of the organic mixture called ‘tannic acid’ but if we recognize that it is typical then each molecule can be approximated to contain 25 phenolic groups and 10 ester linkages. The phenolic groups alone would comprise over 15 hydrogen bond acceptors and 25 hydrogen bond donors.

 Opportunity for Undergraduate Chemistry Major Project

Could a hydrotrope of tannic acid selectively extract organic compounds dissolved in organic solvents typically used in industrial process chemistry? Could it simply solve otherwise difficult separation problems in the fine chemicals or pharmaceutical products industries? These are important questions that could be answered by the research for an undergraduate organic chemistry major's project.

The Use of Methyl or Ethyl Salicylate to Crystallize Solutes Insoluble in both Hydrocarbon Liquids and Water

The following is a research idea. As far as KiloMentor is aware It has not been demonstrated. Before any new research experiments are started an up-to-date literature search is recommended.

A very large number of organic compounds are essentially insoluble in both pure hydrocarbon solvents and in water. As such they would be expected to also be insoluble in a two-phase mixture of water and hydrocarbon. Solutes that belong to this large group would be candidates for a crystallization/recrystallization procedure that, as far as I know, has not been tried to date.

Methyl and ethyl salicylates are very low melting solids and high boiling liquids: methyl salicylate mp -8.6 C; Bp 220-224 C; ethyl salicylate mp 1 C; Bp 232.5 C.

They share another common property. When stirred with aqueous alkali they are hydrolyzed to 2-hydroxybenzoate salts. What is less commonly recognized is that the presence of a separate hydrocarbon phase would not effectively inhibit this hydrolysis. The reason: the free phenolic substituent essentially drags the ester into the aqueous phase where the base attacks the ester functionality irreversibly after which it no longer has any affinity for the hydrocarbon layer. 

Unlike hydrocarbons or water, these compounds will be good solvents for a wide variety of other organic materials. They can interact using Van der Waal dispersion forces, dipole-dipole interactions, and hydrogen bonding using both the phenolic hydrogen bond donor and the ester carbonyl hydrogen bond acceptor. Furthermore, these compounds are not particularly expensive and are readily available at industrial scale. They have been demonstrated to be safe. Methyl and ethyl salicylates are flavouring and perfume chemicals. 

 
Suppose we choose to dissolve a solute of interest in a combination of a highly apolar poor solvent, like the hydrocarbon heptane for example, and as solubilizing agent methyl or ethyl salicylate. Such a combination will have the property of having a boiling point at least as high as the hydrocarbon used but will have the enhanced dissolving power provided by the additive. When the mixture is all a single solution it is cooled to ambient temperature and an immiscible aqueous solution of base is added. Even with only very weak stirring hydrolysis in the two-phase medium will result in the salicylate being taken into the aqueous phase. Now with its solubilized degraded neither hydrocarbon nor aqueous phases will have appreciable solubility for the substrate so it should slowly crystallize out.

Wide Range of Acceptable Solutes

Even solutes containing functional groups sensitive to aqueous alkali can be expected to safely undergo this treatment. Molecules without active hydrogens (such as phenols, carboxylic acids) will not be extracted out of the hydrocarbon phase and so will be protected from significant alkaline hydrolysis.

Hypothetical Examples

An example of a preparation that might be improved using this methodology can be found in Organic Synthesis Col. Vol. 1 pg. 60 Anthrone Synthesis. The anthrone is finally crystallized from 3:1 benzene and petroleum ether. It is reported that about 12 g of the 3:1 mixture is required for each gram of anthrone.  The yield percent recovery is 62/82.5. An effort is made in this preparation to recycle mother liquors and this reuses about 2/3 of the liquid. The anthrone is much more soluble in benzene than in the petroleum ether antisolvent.  It would be interesting to see how the purification would proceed with heptanes as antisolvent and one of these hydroxyl benzoate esters as the solvent with dissolution at the reflux temperature of heptanes.

Another opportunity to use this technology seems to be presented by the bromination of anthracene to 9, 10-dibromoanthracene. A process is described in Organic Synthesis Col. Vol. 1 pg. 207. This procedure uses carbon tetrachloride as solvent. This would be unacceptable in scale-up today since carbon tetrachloride is a recognized carcinogen.  It might work to brominates anthracene with bromine in heptanes. The dibrominated product is likely to be poorly soluble in heptanes and anthracene itself would only be somewhat better. In the heated reaction mixture, the anthracene would probably dissolve enough to allow the reaction to proceed. At the end the crude dibromoanthracene would be precipitating. To recrystallize and recover the solvent one of our salicylates could be added with heating to get solution; the combination then filtered hot; dilute aqueous alkaline to hydrolyze and extract the hydroxyl benzoate ester. Since the 9, 10-dibromoanthracene would then become insoluble both in the aqueous and the hydrocarbon phases it would crystallize.

Other Possible applications

Other compounds from Organic Synthesis that could benefit from purification from a two-phase mixture of aq. alkali and high boiling hydrocarbon solvent: desoxybenzoin pg. 156: desyl chloride pg. 159; dibenzalacetone pg. 167; ethyl 2,3-dibromo-3-phenylpropionate pg. 270; m-nitroacetophenone pg. 434; Organic Synthesis Col. Vol. III acenaphthenequinone pg. 1; acenaphthenol-7 pg. 3;