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.

A Proposal for Separating a Mixture of Water and a High Boiling Dipolar Aprotic Solvent from a Drown-Out Precipitation.

Frequently in organic synthesis, a product synthesized in dimethylformamide (DMF), dimethylsulfoxide (DMSO) or another high boiling dipolar aprotic solvent is precipitated by adding a substantial excess of water. At present, this drowned-out aqueous solvent mixture cannot be economically recovered but needs to be sent for destruction.  This is wasteful and environmentally questionable. It is also more expensive than burning a completely combustible, purely organic waste. A drown out also usually raises the point of maximum volume thereby reducing throughput.

These difficulties separating away dipolar parotid liquids are not only because there is a strong affinity between these higher boiling organics and the water but also, because after a drown-out there is just such a high proportion of water. 

 Pyridine Treatment

Let us do a thought experiment. Imagine what would happen if pyridine, which forms a binary, minimum-boiling azeotrope with the water in the mixture, is added. Pyridine makes a stronger hydrogen bonding possibility available to the water.  The result may be that pyridine will form an azeotrope with water, which can be removed as the low bp. azeotrope at 92.6 C.  If this were to be the result the still-pot residue would be DMF. A further advantage of this method of purification would be that the potential pyridine impurity left in the residual DMF  is aprotic and is therefore unlikely to interfere in reactions requiring anhydrous conditions. That is, the recovered DMF is aprotic and can probably be reused.

But wait a minute, we now have a large amount of a homogeneous solution of pyridine and water; the pyridine/water azeotrope, which is 57% pyridine and 43% water. Are we better off or have we just changed one problem for another while spending more time and more money?

Pyridine Recycling

The difference is that this mixture can be separated into two liquid phases by the addition of sodium hydroxide.  The separated pyridine layer can be further dried with solid sodium hydroxide or can be used in a wet condition to purify more DMF. The alkaline water can be used in the plant to neutralize an aqueous acid fraction from any other process in preparation for sending it to the sewer.

Imagine a mixture containing 90% water and 10% DMF. Add to this a convenient portion of pyridine and distill the water/pyridine azeotrope away from the DMF containing mixture. In the distillate vessel, the azeotrope comes into contact with a reservoir of solid sodium hydroxide or perhaps just liquid caustic. The distillate separates into a strongly basic aqueous lower layer and an upper pyridine layer. The pyridine layer is led back into the still pot to remove more water/pyridine as an azeotrope. When all the water is transferred out the head temperature rises and the pyridine is distilled leaving purer DMF separated from all the water! If there is any pyridine residue in the DMF it does not contain any available hydrogens and may be suitable for reuse as is. The pyridine fraction is drummed off for reuse and the aqueous alkali kept to neutralize another plant waste.

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.

Direct Isolation as a Method in Process Development

In  2004, Neil G. Anderson wrote an article,[ Organic Process Research & Development, 2004, 8, 260-265] where he assessed the benefits of what he called direct isolation processes. Anderson is the author of the finest book about organic process development, Practical Process Research & Development.  In the ‘direct isolation’ article he described three choices for work-up and isolation: direct isolation from the reaction mixture, extraction followed by isolation, and telescoping. 

Kilomentor opines that such categorization is too simple, while providing no useful organizing insight to balance the inexactness introduced by the simplification. Rather, what is needed in the 21^st century to advance the process development art is a more widely held view that quench, purification, and isolation each have many options and these combinations of choices need to be tailored to the particular instance as carefully as the chemical reaction conditions to which the overall work-up applies. 

Anderson quotes with approval P. Zurer [Chem. Eng. News  [2000, 78(1), 26] “In a typical chemical operation, 60-80% of both capital expenditures and operating costs go to separations.” Dr. Anderson and I would agree that in process development, where optimization is cost driven, more attention needs to be directed to fishing the desired reaction product cleanly out of the chemical soup; that is, from the reactor contents. For too long chemists have been disadvantaged by training that taught them to “work up the reaction in the usual way.”

Anderson’s simplification makes it more difficult to consider separations conducted after a number of treatments of the reaction mixture, such as, to identify just a few examples, by separation by solvent exchange, by-product precipitation, product derivatization, clathrate complex formation, scavenger resins, or capture and release resins.

Unisolable Reactive Intermediate Compounds

When we organic chemists talk about reactive intermediates, often we mean transition states like carbonium ions, radicals, or carbanions that are undetectable by normal analytical methods and that exist at such low levels that they can be treated kinetically as being at some constant but very low concentration throughout a chemical transformation. In addition to these; however, there are authentic substances existing at analytically detectable concentrations that are simply too unstable to be isolated in good yield under convenient conditions. They are also called reactive intermediates. They are intermediates in a reaction sequence rather than a single reaction. The greater numbers of these situations arise when compounds are not stable at convenient isolation temperatures or when compounds are too reactive to be concentrated down to a solid or neat liquid state.  An answer for the problem of handling most of such substances is to ‘telescope’ the first reaction into the second. No attempt is made either to store that first unstable compound or to remove the diluting reaction milieu that surrounds it.

Flow Systems

Some such reactive intermediates are too unstable even for these methods to work. Sometimes the conditions required to obtain a practical rate of formation of the intermediate are still too vigorous to allow it to accumulate without further degradation. For such materials some sort of flow system is required to control how long reagents and starting materials are in contact before the accumulating intermediate is carried into an environment where the subsequent transformation can take place. Such flow reactors are a popular expedient today; however, such methods are not new and do not have to be expensive or high tech.

Flow reactors can be advantageous when the reaction mixture passes through a very viscous intermediate stage where much stronger stirring is required {Om P Goel, Continuous reactor model for the use of butyl lithium in the pilot plant, 1974 ???] ; this can be frequently caused by the low temperature required for the stability of the intermediate.

Sometimes the intermediate is too unstable to remain in the reactor during the time required for the mixing of the reagents on a large scale [J.A. Foulkes and J. Hutton, Synthetic Communications, 9(7), 625-630 (1979).]