Mixed Xylenes as a Possible Extraction Solvent that is Immiscible with DMSO, DMF, and Trichloroethylene (TCE)

 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.

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.

Phenylboronic Acid: A Functional Tag to Enable Simple Removal of Excess Reagent or Coproduct using Chromotropic Acid

Chromotropic Acid for Extracting Boronates

The KiloMentor Blog articles emphasize ways to make the workup, separation, and purification of the product from organic reactions more cost-effective. Often this is enabled by phase switching methods that quickly take the desired material into one bulk phase and byproducts, coproduces, and the processing chemicals into another.

One way to dot this is to use a reagent or coreactant that has built into its structure some functionality that allows it to be subsequently extracted into an aqueous phase. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is an example of such a reagent. The pendant dimethylamino functional group makes an excess reagent or coproduce or byproduct basic and so soluble in aqueous acid.

A functional fragment that can be used in this way but has rarely been adopted is the p-dihydroxy-boryl benzyl function.  This substructure appears in the Dobz protecting group for peptide synthesis [D.S. Kemp and David C. Roberts, Tet. Lett. 52, 4629-4632, 1975]. The dihydroxyboryl group forms a strong covalent linkage with the sodium salt of chromotropic acid [1,8-dihydroxynaphthalene-3,6-disulfonic acid] which is very soluble in water.

In the absence of complexing species, boronic acids are in reversible equilibrium with their cyclic trimers and water. Other species containing the group may be partially converted to Boronic anhydrides.

Although many reactions can be conducted in the presence of the free Boronic acid function  as a second option the Boronic acid can itself be protected as the N-methyldiethanolamine complex. N-methylethanolamine is of course itself readily taken into water in a workup. 

Persilylation and its Uses

 

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 at least one protic component and such a solvent would use up all the silylating agent and prevent substrate 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 are both aprotic and only partially miscible. 

KiloMentor proposes that silylation of all the components of a mixture to be separated should either decrease some and retain unaltered some of their polarities and so 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 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 applicable functional groups in all the components in a reaction mixture is necessary. A further practical consideration is that such silylation procedure must be inexpensive; otherwise, the additional reagent cost will make the procedure uncompetitive with alternative separation means.  Fortunately, it has long been known that there are catalysts for silylation, which allow chemists to use the convenient and inexpensive hexamethyldisilazane reagent for 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.

Silylation Catalyst Structures

Although many catalysts are claimed (there is a corresponding patent  EP81200771.4 now expired), five were used in 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 silylating reagents are added and the mixture is analyzed as the competitive silylation proceeds 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 either a complete or another 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  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.

Another Possible Approach

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 sterically demanding silylating agent one could try to get kinetically controlled silylation.

The Potential Use of Acetic Anhydride/Acetic Acid for Enabling Solvent Switches during Work-Ups

Each reaction in a chemical process has solvents in which the conversions works better and the preferred solvents for consecutive reactions in a scheme are usually different. As a consequence, performing solvent switches is essential for telescoping process steps thereby avoiding unnecessary intermediate isolations.

The boiling points of acetic acid and acetic anhydride are respectively 117 and 140 C. Both acetic acid and acetic anhydride are quite inexpensive and they are biologically trouble-free.

Acetic acid is infinitely miscible with water and is an excellent solvent for broad classes of substrates. Mixed solutes dissolved in acetic acid lead upon water addition to decreasing solubility of most organic compounds.

Acetic anhydride is a solvent that reacts with solute molecules that have nucleophilic functionalities and particularly those with what is termed 'active hydrogens'. Because of its even higher boiling point, acetic anhydride can chase many lower boiling solvents during distillation. It can then be, itself, converted by hydrolysis to acetic acid, optionally neutralized with aqueous alkali, and washed away from lipophilic materials. Heating a solvent mixture in which acetic anhydride is a constituent dries it. Only enough acetic anhydride needs to be added to a crude product to provide liquidity, then distillation instituted until all the first reaction solvent has been removed. Even if an acetate ester or amide is formed during isolation, that can be reversed by alkaline hydrolysis after the solvent of the first reaction is removed.

Because acetic anhydride has a bp of 140 C, it can chase many different first solvents. Just considering those that boil above 60 C they include diisopropyl ether, pet. ether, carbon tetrachloride, butyl chloride, methyl ethyl ketone, benzene, cyclohexane, chlorobenzene, acetonitrile, methyl chloroacetate, 2-nitropropane, MIBK, nitroethane, toluene, 1,1,2-trichloroethane, trifluorotoluene, 1,4-dioxane, nitromethane,  methylcyclohexane, heptane, propionitrile, cyclohexene, 1,2-dichloroethane,  fluorobenzene, 1,2-dimethoxyethane, 1,1-diethoxymethane, trichloroethylene, tetrachloroethylene, dimethylcarbonate, and diethylcarbonate.

 

Consider for example acetic anhydride’s potential for changing from the high boiling solvent chlorobenzene to ethyl acetate. In such a scenario, a mixture of chlorobenzene and acetic anhydride could be distilled to remove chlorobenzene and some acetic anhydride. The still-pot residue would comprise acetic anhydride and non-volatile reaction mixture components. This residue does not solidify because of the presence of the acetic anhydride. The minimum stirrable volume is maintained. Water is added along with the new second solvent which must be water-immiscible, in this case, ethyl acetate. Dilute mineral acid or base may be added to accelerate hydrolysis of the acetic anhydride. The acetic acid or acetate anion dissolves in the aqueous phase and is cut away. The reaction mixture is left dissolved in ethyl acetate.

In a different scenario, if the first solvents are low enough boiling, acetic acid itself can serve as the chase liquid for distilling away the first solvent. The product may not be particularly soluble anhydrous acetic acid or the acetic acid can be subsequently diluted with water used as an anti-solvent to cause precipitation or the acetic acid can be optionally neutralized and washed away with water after adding the new water-immiscible second solvent.

Acetic acid itself forms azeotropes with many common solvents that reduce the temperature at which they can be removed: butyl ether, chlorobenzene, cyclohexane, cyclohexane, tetrachloroethylene, trichloroethylene, toluene and xylene are among these.

A Novel and Possibly Versatile Method for Separating of Aldehydes Alone

For 40 years I have been thinking about commenting on this article published in the Chemical and Pharmaceutical Bulletin in 1980. In that year Shunsaku Ohta and Masao Okamoto published a three-page communication that taught a simple method for extracting only aldehydes into an aqueous layer and then recovering them in pure form and high yield. I expected to find more complete details later along with experimentation to support a hypothesis for the mechanism of action and I expected many subsequent applications of the method. Nothing could be further from reality. There does not seem to have been any further work or use!

What the authors taught in Chem. Pharm. Bull. 28(6) 1917-1919 (1980) was that a 1.2 M 6-aminohexanoic acid sodium salt solution could quantitatively carry aldehydes, from mixtures of substances comprising at least one aldehyde dissolved in either diethyl ether or diisopropyl ether, into an aqueous phase. Then, after separating the aqueous and organic solvent layers, the aldehyde could be liberated by acidifying the aqueous phase to pH 4-6 and back extraction into an organic phase….. free of non-aldehydes (including ketones). 

6-aminocaproic acid (6-aminohexanoic acid) is cheap. It is the monomer for making nylon! 

The data in this communication shows that the method is not completely selective for aldehydes. Cyclopentanone was partly selected by the reagent, even though cyclohexanone was completely excluded.  Aliphatic aldehydes gave emulsions but these were cleared by adding some isopropanol.

So this procedure seems very practical. Of course, it may not work! Perhaps that is why nothing more has been written about it. But surely it is worth investigating further.

The authors pictured the isolation as proceeding through the formation of the imine, the covalent bond of which pulled the aldehydic moiety into water courtesy of the sodium carboxylate functionality on the other end of the reagent. The authors do not offer any explanation, however, of why the equilibrium so greatly favors the imine. 

Also left hanging- how high can the molecular weight of the aldehyde be and still have it successfully transferred to the aqueous phase? What organic solvents can be used besides diethyl ether or diisopropyl ether? All remains clouded.

Reactive Distillation using Enamine Formation for Separating Different Ketones also useful for Separating Ketones from non-Ketones

Two ketones with different steric surroundings, when caused to react with an insufficient quantity of an appropriately selected cyclic secondary amine, will have different rates of formation and different equilibrium concentrations of enamines.

For example, according to Peter W. Hickmott in Tetrahedron 38, 1975 (1982), a mixture of non-, mono-, and di-methylated 4-t-butyl-cyclohexanone was separated by first allowing the mixture of ketones in refluxing benzene to react with gradually increasing amounts of morpholine until gas chromatographic analysis indicated that all of the non-methylated fraction had disappeared owing to the formation of its examine. Then the unreacted ketones were removed and treated with increasing amounts of the more reactive amine pyrrolidine until gas chromatography show all of the monomethylated compounds had disappeared by forming enamines. The dimethylated ketone could then be distilled off and separation was complete!

A small steric or molecular weight difference is magnified into something that allows simple separation.

It should be obvious that the same methodology in a simpler form could be applied to separating a mixture of ketones and non-ketones. The ketone fraction would be derivatized with an appropriately reactive cyclic secondary amine, the catalyst neutralized and the fraction (not changed in properties) separated. The ketone fraction could be converted back from enamine by acid-catalyzed hydrolysis and the secondary amine taken into acidic water.

Precipitation and Isolation of Organic Carboxylic Acids, Sulfonic Acids and Sulfinic Acids from Solution or Reaction Media.

Arylmethylisothiuronium Salts

Ionizable acids are intermediates preferred by KiloMentor in organic synthesis schemes because they are more easily separated in pure form whether by extraction of the anions into water or precipitation of insoluble salt compounds.

Arylmethylisothiuronium salts are useful intermediates for precipitating these organic acids, particularly if (i) the molecular target contains another functionality that is sensitive to aqueous alkali or (ii) the entire target molecule is water-soluble. The arylmethylisothiuronium salt reagents themselves are decomposed by aqueous alkali to liberate arylmethylthiols, so conditions must be kept slightly acidic during all operations using them. 

Carboxylic Acids

Carboxylic acids are first converted into sodium salts by reaction with sodium alkoxide in alcohol and then mixed with a solution or slurry of the arylmethyl-isothiuronium halide in alcohol. The salt crystallizes out. It is important for carboxylic acids that the liquid be water-free and the pH not at all basic.  Salts of weak acids such as the carboxylic salts, in the presence of any water, can partially hydrolyze back to free acid and sodium hydroxide which creates a basic solution which then will degrade the isothiuronium reagent. 

The isothiuronium derivative can be formed in water so long as the formation of the carboxylic acid salt is never completely neutralized. This is accomplished by only adding alkali until methyl red changes color. Another literature citation proposes that the neutralization be done to the point of the color change of phenolphthalein followed by the readdition of acid until the color disappears.

Sulfonic and Sulfinic Acids

Salts both of sulfonic acid and sulfinic acid anions and arylmethyl-isothiuronium cation are preferably formed by mixing aqueous solutions of the reagent and the alkaline metal salt of one of these acids. These precipitations can be done in water which gives much higher yields of these crystalline products. Degradation from adventitious base is less likely because for these stronger acids there is no propensity to hydrolyze the salts to create an alkaline solution.

The regeneration of all  the purified acids is done the same way. In a mixture of an organic solvent immiscible with water and water acidified with hydrochloric acid, the isothiuronium salt is added and stirred vigorously. The strong mineral acid partially or completely protonates the organic acid whereupon it dissolves into the immiscible organic layer leaving the regenerated arylmethyl-pseudothiuronium chloride in the aqueous hydrogen chloride mixture. Heating the aqueous acid phase dissolves the regenerated reagent which then crystallizes when the solution is cooled.

The purified organic acid is recovered from the organic solution by any convenient means.

It seems likely that carboxylic acids in these isothiuronium salts can be liberated by the more acidic alkylsulfonic acids; for example by methanesulfonic acid.

It might well be that any O-acid with at least two tautamerically equivalent oxygens could form these derivatives: such as alcohol sulfonic acids, sulfamic acids, or phosphonic acids. This is something that can be explored further. I do not have any information on these.  

Using Functionalized Polymers at Scale in Process Chemistry

Functionalized polymers can serve as scaffolds for process intermediates, as reagents, as co-reactants, as catalysts, or as a solvent phase; however, using polymers in process chemistry violates “atom economy” in a massive way. Using polymers in any capacity adds to the mass used without incorporating that mass into the product; therefore, using functionalized polymers must provide a large compensating benefit.

The compensating benefit could be:

In safety and regulatory affairs by avoiding

• smelly reagents like sulfides and thiols 
• explosive reagents such as aromatic peracids, sulfonyl azides
• toxic waste by immobilizing Cr, Sn, Se, Ni
• trace heavy metals that are avoided Ag
• reagents that are toxic: crown ethers, HMPA cosolvent, cryptates
• reagents that cause sensitization: carbodiimides

Avoiding normal small-molecule reagents that cause difficulties in work-up

• triphenylphosphine oxide
• ureas from carbodiimides
• emulsifiers
• phase transfer catalysts
• mineral or organic acids by replacement with cation-exchange resin
• mineral bases that introduce water-soluble alkali and alkali earth salts with anion-exchange resins

Avoiding reagent degradation (where the regular reagent is too unstable)

• Lewis acid impregnated microporous resin AlCl₃ impregnated into carbon
• chromic acid impregnated charcoal
• potassium impregnated graphite
• polymeric trityllithium

Polymeric Protection as a Phase Tag

• scavenger resins to remove residual excess reagent
• starting reagent so that an excess can be used
• capture and release purifications
• cosolvent extraction phase (macroreticular polystyrene)

Removal of Trace Components by selective reactivity

• removal of oxygen (example)
• removal of heavy metals (like using EDTA)
• removing singlet oxygen
• removal of water: carboxymethylcellulose sodium, butyrolactone 
• removal of organic solvents: molecular sieves
• removal of carbonyls: semicarbazide on silica; site isolation
• mono protection of symmetrical substrates
• telescoping process steps using two antagonistic reagents immobilized on separate resins such as periodic acid/ borohydride for first cleaving then reducing 1,2-diols

Recovery of Expensive Catalysts

Solvents

• polyethylene glycol as a solvent for sodium hydroxide or potassium hydroxide
• polyethylene glycol as a dispersing agent during solvent switches based on evaporation to dryness
• polyethylene glycol as distillation chaser

Because of the lack of atom economy to be cost-effective reactions using polymers as processing chemicals or reagents should be used in the latter portion of reaction sequences when small improvements in yield can produce overwhelming cost benefits.

30% Acetic acid- 70% Water and Methylene Chloride: Two Liquid Phases for Partition Extractive Work-ups

Because Kilomentor puts a huge emphasis on simple, rugged, powerful separation methodologies, I am very interested in pairs of liquids that are not miscible with each other but where both have good solvent properties for a substantial range of  organic compounds. The reason is that liquid-liquid extraction is a simple and scalable purification method.

I have in my old laboratory notes mention that a mixture of two phases: one, methylene chloride, and two, 30% acetic acid-70% water, was used to remove the non-polar contaminants from a peptide mixture made up from among neutral amino acids. It seems to me that the addition of the very good solvent acetic acid will have increased the number of polar or semi-polar substrates so substantially in this predominantly aqueous phase that it in competition with methylene chloride could separate some important mixtures. Furthermore, the dissolving power of methylene chloride probably can be further modulated by adding into it toluene or hexanes for example.  

Switching Solvent at Scale: Using a Minimal Stirrable Volume Chaser

Working at laboratory scale one can switch from a reaction solvent to a work-up/extracting/crystallizing solvent by evaporating the reacting solvent to dryness on the rotary evaporator adding the second solvent and scrapping and stirring the oily neat solid off the walls of the flask and back into solution. So long as consideration is given to not decompose the solutes there is no problem.

With a few kilograms, using a large rotovap containing polypropylene beads to trap solids, the same thing can be done. The free-flowing beads trap the solutes; then, they can be redissolved in the second solvent and the polypropylene beads filtered.

In the pilot plant removing polymeric beads from the reactor is not possible. Evaporation to dryness is not possible. A possible solution might be to add into the reactor an inert, high boiling fluid in a volume such that the total volume of the non-volatile solutes plus this fluid reached the minimum stirrable volume. Now the first solvent could be distilled out of the reactor completely because at the end there would remain the minimum stirrable amount of non-volatiles containing all the non-volatile reaction pot contents.

What should be the properties of a minimum stirrable volume chaser? Well if we are going to get it separated from the reactor components of interest by extraction it must be immiscible with some standard organic solvents. This suggests that if the reaction products of interest are at least moderately polar the volume chaser should be a high-boiling paraffin. Such a chaser would be immiscible with either methanol or acetonitrile. Polar or semi-polar compounds would easily be extracted out of the paraffin phase. The paraffin chaser could be saved, drummed off, and reused for repeats of the same reaction.

Traces of paraffin can be removed from methanol by forming the insoluble complex with urea. The complex and excess free urea would be filtered off from the methanol solution.

In the event that the desired reaction products are more nearly apolar, the volume chaser should be itself polar. Liquid polypropylene glycol or glycerol can be used. These will work because the desired reaction components as an oil in either of these can be separated by liquid-liquid extraction with any organic solvent that isn’t appreciably miscible with them. Traces of either polypropylene glycol or glycerol can be precipitated as complexes with anhydrous calcium chloride at an appropriate point in the work-up.

A final possibility is to use a chaser fluid that can be removed in some other way. A possibility of this type would be to use acetic anhydride bp. 140 C which would drive over many solvents that are not reactive with it and that can be subsequently hydrolyzed to acetic acid which can be removed in water followed by an aq. bicarbonate extraction.

In a similar way, quinoline could be used as a chaser then washed out as a salt in water and recovered by subsequent basification of the aqueous extract.     

The 1,2-Diol Functionality as a Possible Phase Separating Tag

In CA2677670, a monoglyceride ester is separated from other impurities by absorbing the mixture on silica gel and washing with hexanes/ethyl acetate 90:10 v/v. This was not a column chromatography as can be determined from the experimental details. The 90:10 mixture of hexanes/ethyl acetate (10 ml) was used to dissolve the approx. 16 g of ester and to this solution 40 g of silica gel was added.  The slurry was put on a fritted funnel and eluted with 150 ml of the mixed solvents to remove the impurities. A second elution with 300 ml of ethyl acetate  removed the monoglyceride which was concentrated in vacuo. This seems to show that diols seem to bind tenaciously to polar solid adsorbants.

It is well known that mono alcohols often form insoluble complexes with CaCl₂, LiCl, LiBr, CaBr₂ and MnCl₂ for example. So it not surprising that diols would form strong complexes with such inorganic salts.  As evidence of this there is a patent, US 3,846,450 titled Purification of Oxygenated Compounds that describes the removal of diols by passing a liquid comprising some of these through solid alkali earth halides. This would trivialize their separation from compounds without this substructure. 

It has been reported that complex steroidal and prostaglandin structures can be purified by precipitating as LiBr complexes [GB2094795]. The prostaglandin structures typically contain more than one alcohol functionality. This should increase the likelihood that metal halide complexes with 1,2-diols are more likely to produce solid precipitates.  Kilomentor has already published a note about using such metal complexes to separate alcohols from non-alcohols and some alcohol mixtures from each other.

I have not found work showing that substances containing two or more non-adjacent alcohol groups dependably form lithium bromide or calcium bromide precipitates even though the work with lithium bromide and prostaglandin intermediates is promising in this respect. What is clear is that neutral 1,2-diols can be separated from other functionalities ruggedly and dependably.The 1,2-diol functionality most probably can be covalently attached to a very wide variety of intermediates as a ‘phase-separating tag’.

 Substrates containing the tag would, perchance, be precipitated by stirring with an inorganic salt in non-polar solvent. It might turn out that the 1,2-diol at the end of a hydrocarbon chain might be a substructure that could control precipitation in a wide variety of intermediates using a standard set of conditions ( a particular salt, precipitating solvent, ethanol catalyst and reaction conditions). It is already known for example that a primary alcohol is preferred to a secondary or tertiary one.

After the terminal 1,2-diol had served its purpose for intermediate isolation/ purification it could be selectively cleaved to an aldehyde or cleaved and reduced to a primary alcohol with one  fewer carbons than the diol. The functional group would be expected to work as a phase-separating tag best when the other functional groups in the intermediate were not polar ones that could also interact strongly with the inorganic salt.

It seems that whether a solid complex is formed may depend upon both the crystal lattice energy of the complex and the energy of the crystal lattice of the salt itself. As Sharpless notes, [K.B. Sharpless, A.O. Chong, and J.A. Scott, Rapid Separation of Organic Mixtures by Formation of Metal Complexes, J. Org. Chem., 40, 1252 (1975)}, whether they form solid complexes or not the alcohols do cause the dissolution of the calcium chloride into the hexane. Another important observation provided by Sharpless et al. was that mixtures of alcohols often dissolved but did not even partially precipitate under the complex forming conditions even when the pure components of the mixture formed solid calcium chloride complexes when treated individually but separately. 

Why some alcohols form solid complexes and others just dissolve the inorganic salt ,but do not precipitate, has been hanging unsolved for a long time. The Sharpless strategy has never become popular. This is because, according to a personal communication from Sharpless himself, the best conditions for forming and precipitating the complexes were unfortunately not those recommended in his article. Not a 2:1 molar alcohol inorganic salt ratio, but a large excess of inorganic salt works best taking into account more cases. Perhaps the alcohols and inorganic salt form oil-in-water or water in-oil emulsions which only occasionally break down to precipitated solid. 

If the problem is emulsion formation it might be important to remove completely any residual water. Using aprotic solvents that have fewer degrees of freedom themselves might help. Cyclohexane and diisopropyl ether might be tried. Diisopropyl ether seems to be the solvent of choice when it is difficult to get regular crystallization. Patent GB1555968 suggests that methyl isobutyl ketone (MIBK)or methyl n-amylketone are preferred candidates to form insoluble complexes, at least when calcium bromide is used.

Clearly solvents must be used that do not themselves dissolve these divalent inorganic salts because such solvents present in so large an excess would easily out compete substrates.  Hexanes, methylene chloride, MIBK and methyl n-amyl ketones would meet the criterion of not dissolving much salt alone.

Besides the equilibrium effect sometimes giving rise to useful precipitation there is probably also a kinetic effect upon whether the precipitation/crystallization provides purification. The limited data could be interpreted as suggesting that small alcohols exchange more rapidly than large alcohols and small alcohols, present catalytically, promote exchanges. 

Using a Sulfur Tag for Separations both in the Lab and At Scale

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 section 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, 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 support 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 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-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 irreversibly 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. 

The Use of Silver Nitrate Complexing to Separate Olefin Containing Compounds

In Organic Synthesis Coll. Vol. III a mixture of cis and trans cyclooctene is separated by mixing somewhat more than two molar equivalents of an aqueous silver nitrate solution with a pentane solution of the cis and trans compounds. The cis compound does not form any adduct and so remains in the pentane solvent. With vigorous stirring the trans compound forms a complex and dissolves in the aqueous phase. Although silver is an expensive reagent, , at least in principle, it is recoverable, so it can be considered for use at scale. Winstein and Lucas studied the complexes formed between silver nitrate and unsaturated hydrocarbons and found that in some cases these are solids useful for isolation and purification.[J. Am Chem. Soc. 60, 836 (1938)]. Complexes that are solids can be recrystallized, often from hot alcohol. It is not clear whether functional groups besides double bonds interfere with separation in this way, although only hydrocarbons have been described in the literature. It is not apparent why a number other functional groups would be incompatible with the method. It may just be that, when other functionalities are present, there are better known options for separations.

The Diels-Alders adduct between norbornadiene and cyclopentadiene contains two double bonds and forms a 2:3 hydrocarbon/silver nitrate adduct [Am. Soc. 81, 4273 (1959)]. The Diels-Alder adduct between norbornene and cyclopentadiene contains only one olefin group and was purified using its 1:1 adduct [Am. Soc. 86, 2188 (1964).].From work with the mixtures of 1,3; 1,4; and 1,5- cyclooctadiene, it has been shown that silver nitrate forms complexes with each of these, but they have different stabilities, and can be separated by using different temperatures. The weak complexes are only isolable at low temperatures [J. Chem. Soc. 312 (1954)]. The natural triene humulene was purified as a silver nitrate complex containing 2 molar equivalents of silver nitrate [Australian J. Chem. 14,272 (1961)][Tet. Let. 1977 (1965)].

It is interesting to speculate whether an aqueous solution of silver nitrate could be used to treat a mixture of olefin and the dihalocarbene adduct to remove the olefin. The dihalocarbene adduct would be expected to be reactive with silver nitrate if they were both in a homogenous solution but if the dihalocarbene adduct was in a saturated hydrocarbon solvent and the silver nitrate was in water, they might not come into sufficient contact to react. It might also be a problem for complex formation if the olefin that one sought to complex was itself not sufficiently soluble in water to allow reaction.

Use in Column Chromatography

Olefin containing compounds are separated on reverse phase columns when silver nitrate is dissolved in the mobile phase. It would be interesting to see whether the reverse phase HPLC mobility of unsaturated compounds in an aqueous silver nitrate eluate might give an indication of their complexing ability.
 

Liquid-liquid Extraction

Silver nitrate in methanol improves the separation of saturated fatty acids from unsaturated acids that can be held in solution better when silver nitrate is added. This suggests the possibility of liquid-liquid extraction between pentane or hexane and aqueous silver nitrate.