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. 

Choose Moderate Reduce Pressure for Distillation At-Scale

The KiloMentor Blog has highlighted methods for isolation and purification from transformations at scale. One might think that a good place to look for examples of such procedures would be the famous series, Organic Syntheses. This doesn’t turn out to be the case. Organic Syntheses procedures may be good for making multigram samples of intermediate molecular weight intermediates but the techniques used very frequently have no kilo scale equivalent. The most common isolation/purification method used is simple or fractional distillation usually under some vacuum. From my limited experience, it is used in more than 50% of the procedures.  Increasingly in the more recent submissions, some chromatography is used and this is even more unacceptable for large scale work.

Moreover, the distillations are most often performed at diminished pressures that are not readily accessible using standard process equipment. It is a rule of thumb for the plant to not count on getting reduced pressure below 50 mm of mercury. In a sample of 63 procedures I examined at random, only 10 distillations were done at or above this pressure. Nine were performed between 20-49 mm; 22 from 5.0-19 mm; 11 from 1.0-4.9 mm; six from 0.2-0.95 mm; and 5 less than 0.19 mm.

The Pilot Plant Test

Although it may be true that the first pilot plant reaction in a process step development should be done as close as possible to the preferred laboratory protocol, it is not true that the sampling for this pilot plant run should be no more substantial than that in the lab. Because a pilot plant test is so expensive, provision should be made so that, if it results in unpleasant surprises, it makes the investigation easy by providing bountiful data to point unambiguously to a most probable cause for the deviation from the expected result.

It is fair to say that in the first pilot plant run, one needs a convincing reason for not taking a sample at each point in the process where the reactor contents are homogeneous- not just at the points where a regular in-process analysis is planned in the final batch sheet, after optimization.

These samples are of two types. One type is forensic samples.

 These need only be examined when there is a deviation that needs to be investigated. The second type are samples that are used to simplify the process as for example to determine the most efficient number of washes, the best volumes of washes and to obtain a mass balance by determining in what discarded phases product was thrown away.

When samples are taken, some of these samples will be kinetically unstable-that is the reaction is continuing to proceed in them even after the sample is taken. For these kinetically ’live’ samples the best course is to take them on to final product in the laboratory. To do this the sample should have the reactants completely added and should be representative of the reaction mixture. Reaction mixtures that are heterogeneous should not generally be completed in the lab because a negative result will only raise the question, “Is the problem the reaction or the sampling?”

Most often samples of reaction mixtures will be treated with some reagent to stop further reaction and to preserve the stoichiometries present at the time the samples was removed from the bulk reaction.

Sometimes reaction mixtures that are intentionally not quenched even though they are known to be poorly stable are stored in very cold conditions to stabilize them and only used for forensic purposes if and when it is discovered that there was a deviation. If all runs smoothly, they can be discarded.

If the quenched reaction mixture is quite stable, samples should be taken for split run testing of varying work-up variants. Also running the work-up of a known fraction of the reaction mixture in the lab allows a quantitative and qualitative comparison of the yield and purity between lab and plant methods.
If multiple extractions are performed, samples of the discarded phases can be used to determine the mass balance and to predict the most efficient number and volumes for the extraction liquid phases. Because the point of maximum volume often occurs during one of the extraction stages, efficiencies in the extraction can increase the throughput and improve the costing of the process step.

Washing of crystals or of insoluble catalysts or by-products can be important for realizing a good yield. Samples of the filtrate at different points can provide information about the best wash quantities. The effectiveness of the washing of a filtered solid will almost always be very different with the plant equipment compared to the laboratory setup. If centrifugation is used in the pilot plant this is even more often true.

A pilot plant run should never be undertaken until a lab batch has been made and analyzed using the solvents, reagents, and substrates to be used in the pilot batch. That is: substrates, reagents, solvents and catalysts that are to go into the pilot plant batch should be use-tested in the laboratory. This the most fundamental rule of scale up, yet, it is the frequently violated. The reason is that sampling the pilot plant materials is tedious or faces bureaucratic documentation hurdles. One solution is to ask well in advance so that the process development use-test sample is taken when the analytical laboratory sample to verify the certificate of analysis is taken.  

Digestion or Trituration by themselves or combined with Adsorption on an Inert Solid Support

The terms digestion and trituration seem to be used interchangeably by many chemists. In my KiloMentor articles, I consider digestion to be hot trituration.

Trituration

Pure hydrocarbons are used frequently for trituration because in the cold they dissolve much less of most products compared to more polar organic solvents yet they can substantially reduce impurities that are present in small amounts. Thus digestion with hydrocarbon solvents can be used for initial purification of a crude mixture, so long as it is not an oil. If it is an oil, trituration may still succeed so long as enough hydrocarbon triturant is used so that any liquid impurity is only a small portion of the liquid phase.

A rule of thumb might be to triturate mixtures of high molecular weight compounds and distill or co-distill low molecular weight ones before trying to crystallize either one.

The purity of solvents used in crystallization is important because solvent impurities, even other solvents, can retard the rates of both crystal nucleation and crystal growth just like other higher molecular weight reaction impurities can. Because solvent changes on scale are done by solvent exchange rather than by evaporation to dryness and replacement with the new solvent, on scale the residue of the first solvent can be more substantial than one would experience in the laboratory.

Besides the physical property difference between homologous alcohol solvents: methanol, ethanol, propanol, etc., process chemists might be wise to keep in mind that only ethanol has denaturants added to make the ethanol unsuitable for beverages. These denaturants are different for different grades and can interfere with the crystallization kinetics.

Water is the most omnipresent impurity in crystallizations, so much so that in many cases efforts to work free of it are doomed to failure. Poly-hydroxyl compounds such as sugars and glycosides are the common materials most dramatically affected by the presence of water. To illustratw, sucrose of 72% purity has been shown to crystallize twice as fast as a 70% pure sample but only one-fifteenth as fast as the pure sugar. [A. R. Nees and E.H. Hungerford, Ind. Eng. Chem., 28, 893 (1936)].

Water frequently forms a solvate with a compound of interest and this can be helpful, or not, depending upon the properties sought.

Digestion

Digestion is hot trituration with the minimum amount of a poor solvent required to cover a crude solid and make it stirrable. Digestion as a purification method at scale requires some means to obtain an initial crude solid without evaporation to dryness.  Digestion is typically done by refluxing the liquid making up the slurry in order to equilibrate the impurities with the solvent.

In addition to water and saturated hydrocarbon as liquids likely to dissolve only a small amount of the main product in a trituration or digestion, the following azeotropic mixtures, which are either hydrocarbon or water-rich, are suggested. None have been tested.

97.0% water 3.0% acetic acid azeotrope bp 76.6 C

91.0% water 9.0% Benzyl alcohol azeotrope bp 99.9ºC

87.1%heptane 12.9% water azeotrope bp 79.2 ºC

94.4%hexane   5.6% water azeotrope bp 61.6ºC

95.5% hexane 4.5% allyl alcohol azeotrope bp 65.5ºC

97% hexane 3% 1-butanol azeotrope bp 67.0ºC

91.5% Cyclohexane  8.5% water azeotrope bp 69.8ºC

83.7% acetonitrile 16.3% water azeotrope bp 76.5 C

72.9% Allyl alcohol 27.1% water azeotrope bp 88.2ºC

66% Allyl cyanide  34% water azeotrope bp 89.4ºC

77.5% Formic acid 22.5% water azeotrope bp 107.1ºC

Digestion from an Inert Support

KiloMentor has already written about direct isolation on a solid support.

An idea that synthetic organic chemists have apparently not considered up until now is the evaporation of a reaction mixture onto an inert solid material from which byproducts can be digested away using poor solvents followed by dissolving the main product with a good solvent and filtering away from the inert solid support material.  One possible reason for this is that synthetic chemists are not familiar with the properties of pharmaceutically acceptable supports that could be used as the inert material for such evaporations.

The inert solids can be pharmaceutically acceptable tablet excipients such as microcrystalline cellulose, crospovidone, cross-linked polystyrene, calcium sulfate, calcium carbonate, calcium phosphate. They could be heated and stirred to just above the temperature of the solvent in which the reaction mixture is dissolved and the solution of the reaction mixture added to it.

The solvent would be expected to flash distill out of the reactor and could be collected for destruction or reuse.  The method would have a particular advantage in that it could be used for recovering dipolar aprotic solvents which are more difficult to remove.

Similar things have been done. Evaporation of a solution of a reaction mixture onto chromatography media such as silica or alumina has been done to prepare a concentrated band of material that can be spread on the top of a chromatographic column to be eluted with a series of increasingly polar solvents. 

Treatment of a solution of a crude reaction mixture with charcoal has often been done to remove small amounts of non-polar high molecular weight impurities. A paper has been published that illustrates the work-up of a chromic acid oxidation by pouring the crude reaction mixture onto a column of cross-linked, unfunctionalized polystyrene and eluting the column with methanol-water mixtures to remove first the inorganic salts and then the organic products. In this process, the solvent of the reaction mixture is simply diluted with the methanol-water eluate.

In the slightly different process, I am contemplating. The reaction mixture would be added to stirred, warm, cross-linked polystyrene so that the reaction solvent evaporates and leaves the crude product in the solid resin. Then the inorganic components would be removed by digestion or trituration with methanol/water mixtures. Thereafter, the organic compounds would be eluted with a less polar solvent mixture.

Since charcoal has been used as an additive to consume excess oxidant, the first step after reaction completion could be treatment with a small amount of charcoal and filtration followed by evaporation onto free flowing non-functionalized cross-linked polystyrene.

If we can obtain the crude solid solvent-free, we can also adopt the other digestion technologies using poor solvents for the principle product.

Evaporation of a reaction mixture onto a solid polymer is one means to evaporate to dryness; something that cannot be done on-scale in a large stirred reactor.

In Process Controls and Forensic Samples in Chemical Process Development

A pharmaceutical process that has been scaled-up is monitored using the results of in-process controls.  These are tests that, for a particular run, either conform or do not conform to a pre-set limit. If the test conforms, the operators proceed to the next instruction in the batch process, but if the result is nonconforming, the result is reported to the manager who decides what action to take next.  For an in-process test, the actions to be taken are characteristically thought out in advance.  If there is no possible corrective action for an out of specification result, the test is not a proper in-process test but rather just a datum that may be part of the analysis of the result when the final outcome is known.

When a process has been 'optimized', it is taken for granted that it will operate within its control limits and no testing beyond its in-process ones will be required to guide the operators to a successful result.

Pilot Plant Experiments and Forensic Testing.

Although the chemical plant or kilo-lab process can be modelled using a laboratory scale procedure, it cannot be optimized without results from representative samples from the scaled-up process taken at critical decision points in the process.

The pilot plant runs are still experiments, even if the equipment is handled by personnel who are not research chemists.  Although the chemist may think that (s)he understands, for practical purposes, the experimental reaction and subsequent purifications steps being scaled-up, this is at least immodest and usually foolish.  The experimenter is wisest who anticipates the most potential problems and in the beginning collects samples at every convenient sampling point when the process is executed on scale.  That means taking many more samples than simply those which will remain mandatory for in-process control.  These extra samples we will call forensic samples because they are very often only analyzed when the result is disappointing in some respect. These samples can determine what went wrong and how to correct it.

Forensic samples are carefully stored so they will not deteriorate. Forensic samples are not analyzed while the process is running, but are for retrospective testing by the process chemists and may never be looked at if the process runs without any deviation.  

There is only one downside to the collection of forensic samples.  If the process runs perfectly and gives a product of the exact same quality as the laboratory samples but with a lower yield, the question may arise whether these samples could be predominantly responsible for the reduced yield.  Most often the size of the samples or the mechanical losses that can occur when taking forensic samples cannot explain a noticeable reduced yield on scale.  The samples are typically just not large enough compared to the size of the process. Simple calculations, in most cases, will give a pretty good idea of how much yield could have been lost through this extra sampling.

Almost without exception, the forensic sampling will provide an improved opportunity to understand what has caused any deviation from the desired result.

Thorough forensic sampling examines not just the physical phases where you expect the product to predominantly reside. Samples of the waste solids and liquids can also be valuable. Filtrates, wash liquids, filter cakes, and head space gases may reveal where, for example, the missing product has vanished.

Once the process is set, these forensic tests should be removed from the batch instructions. The only tests that should remain in an optimized batch sheet are the in-process tests that are done at the decision points.

Sampling Problems

Obtaining a truly representative sample from a large reactor presents more difficulties than laboratory sampling. For safety reasons, plant samples must be taken without opening the reactor. Most often a dip-tube that runs many meters down into the reactor is used and the sample is removed by suction. There is no way to verify how effective the cleaning between samples is nor is there any way to guarantee that stratification or gradient has not been created in the sampling line. 

Samples that are likely to contain unstable species need to be adequately quenched before labeling and storing them. Samples of distillates, filtrates, washings, and recovered processing solids are easier to handle. 

Emulsifiers, Detergents, and Surfactants in Green Synthesis

Cetyl trimethyl ammonium bromide- A Detergent

As part of the increased popularity of ‘green chemistry’, many persons have considered doing organic chemical synthesis using water as solvent. This may be a good idea or it may be simplistic. Using water avoids organic solvents, but even when there are only small amounts of dissolved or entrained organics, cleaning up waste water so that it can be sent to sewage is neither simple nor green. Destroying water by combustion is expensive. Whatever the outcome of this controversy, detergents, emulsifiers or surfactants, whatever you choose to call them, can cause homogeneous, bulk water to hold substantial amounts of lipophilic materials. Chemicals can react in such media, sometimes with rate accelerations. It is not clear whether these accelerations are caused principally by miscelle formation or phase transfer catalysis or some combination of the two.  

Generally the presence of these amphiphilic substances makes isolation procedures more difficult, because chemical separation at the molecular level is achieved by phase separation at the macroscopic level and an emulsifying agent makes the two most common immiscible liquid phases oil and water, more miscible; therefore, it seems necessary that the surfactant should be destructible so that it loses its ability to emulsify once the reaction is complete and before the separation phase of the process is begun.

An article by F.M. Menger, J.U. Rhee and H.K. Rhee published [J. Org.Chem., 40, 3803 (1975)] is one of the early preliminary explorations. In one experiment, they compared the oxidation of piperonal, mp 36∞ C, using potassium permanganate in water at 55∞C, with and without 0.01M cetyltrimethylammonium bromide.  The authors observed about 33-37% yield without surfactant and 64-74% yield with surfactant.  Surprisingly, the yield appeared to be independent of the reaction time; whether 70, 100 and 150 minutes was used.  This was not further explored even though the authors were aware that in Organic Synthesis Coll. Vol. II this same reaction had been done without emulsifier at 80∞C but with vigorous agitation of the water and molten piperonal phases giving a 97% yield. It may have been that the permanganate was degrading as the reaction proceeded and the oxidizing capacity was over after 70 minutes or less. Another complicating possibility is that at the reaction temperature the permanganate also attacks the bromide in the cetyltrimethyl ammonium salt.  The permanganate could oxidize bromide to bromine and this could in turn brominate the piperonal leading to brominated by-products. This latter suggestion is supported by the fact that in one of two runs of 70 minutes duration, where the emulsifier was mixed with the room temperature potassium permanganate and water and added dropwise to the warm piperonal solution, a yield of 74% was achieved compared to 66% when the emulsifier was all placed completely in the hot water and piperonal mixture before starting to add oxidant.

These authors noted that the time saved from the increased reaction rate with emulsifier present was spent in the extended time needed to get phase separation in the extractive isolation. The experimental portion of the article states that when surfactant was present, 2 hours were allowed for phase separation.

In another trial of the methodology, α,α,α-trichlorotoluene was hydrolyzed by 20% aqueous sodium hydroxide at 80∞C.  Using 0.01M cetyltrimethylammonium bromide the reaction gave a 98% yield in 1.5 hours while without catalyst there was zero yield.  In this reaction, the non-ionic block polymer emulsifier  Brij 35 [C₁₂H₃₅(OCH₂CH₂)₂₃OH ] reduced the time to 11 hours for a 97% yield. No detergent such as sodium lauryl sulphate was tried in these reactions.

David Jaeger worked on this possibility in the 1980s 

Jaeger, D.A.; and Frey, M.R., J. Org. Chem. 47, 311 (1982).

Jaeger, D.A. and Ward, M.D. J. Org. Chem. 47, 2221 (1982). 

Jaeger, D.A. and, Martin, C.A. and Golich, T.G. ????

Craig, A. Timothy G. Golich and David A Jaeger, J. of Colloid and Interfacial Science, 99, 561 (1984).

In reaction using a cleavable surfactant, the type of surfactant and the reagent and conditions for cleavage need to be selected in advance so that the product is inert. 

It is still necessary to be able to cleanly separate the cleaved lipophilic portion of the surfactant from the hydrophobic portion.

If the hydrophilic portion is a di-quarternary ammonium salt it is a possibility that it can be precipitated as the embonate salt. This might be converted cleanly back into a more soluble quarternary ammonium species.

It is also possible, if the lipophilic portion is a straight chain alcohol, it might be separated as a urea complex by crystallizing the complex out from a mixture of urea and methanol.

This problem has been approached in a different aspect by persons who were asking how long chain quarternary ammonium salts could be metabolized.  In these cases the long chain amphiphile was interrupted by an ester which under physiological conditions could be hydrolyzed.

NOTE: This blog article was started at least forty years ago so there is a lot of literature not taken into consideration.  It is probably pertinent whether any degradable emulsifiers are now commercial.