Getting Free from Dipolar Aprotic Solvents at Scale

Obtaining a Reaction Product Free from Polar Solvents: Efficient extraction of highly polar solvents from reaction mixtures.
following the late Dr. Phillip Hultin

 Dr. Philip Hultin was a professor at the University of Manitoba, Canada who passed away in 2018. Although I did not know this man, the following article, which I present with a few edits, is valuable for process chemists scaling up extractive work-ups. Searching Philip Hultin extraction in Google will provide the original unedited article.

The Problem of the Standard Practice

The most common workup for reactions conducted in DMF or DMSO is to drown out (dilute) with a larger volume of water, extract with a solvent such as ether or dichloromethane, and then wash the organic phases numerous times with water.  The shortcoming with this is that dipolar aprotic solvents also have significant solubility in organic solvents and they can also behave as phase-transfer agents drawing a significant amount of the desired reaction products into the aqueous layer.  The whole process can become very time-consuming with multiple extractions and back-washings.

A more effective way, in the laboratory setting, to remove these solvents is a series of separatory funnel extractions that somewhat mimic liquid-liquid partition chromatography.  Indeed, it is a counter-current extraction but wherein only one phase is moving.  The method retains all the lipophilic materials,  does not create large volumes of waste, and reduces the time required to achieve essentially complete separation of dipolar aprotic solvents such as DMF or DMSO from reaction mixtures.

The procedure uses one larger separatory funnel and three or four smaller ones. For laboratory-scale extractions it is convenient to have a rack that can hold all the separatory funnels in a row.  For “large scale” extractions where the first separatory funnel is larger than 250 mL capacity, stands with rings are more appropriate. 

The Laboratory Procedure

1.  After quenching the reaction and diluting with enough ether to easily dissolve the expected products everything is poured into the large funnel #1 and the reactor flask washed with a little ether. There, it is diluted gradually with a generous amount of water. As the water is added two phases start to separate. Doing the addition of liquids in this order may reduce or eliminate the amount of agitation needed to equilibrate the layers; furthermore, the effect of further small increments of water on the volume of upper and lower phases can be more easily assessed and this correlates with the partitioning of the dipolar aprotic solvent.
  2.  Into each of the remaining funnels #2 through #5 is placed a smaller portion of ether.
3.  Funnel #1 is shaken and allowed to settle. 
4.  The aqueous (lower) layer is run out into funnel #2. 
5.  Funnel #2 is shaken, and while it settles, an additional portion of water is poured into #1 and shaken.

6.  The aqueous layer from #2 is run off into #3, the aqueous from #1 is run into #2, and more water is added to #1. 
7.  All funnels are shaken and allowed to settle.

8.  The process of running the aqueous layers into the next funnel in sequence is repeated until all funnels have been shaken with water and the first aqueous portion resides at the bottom of funnel #5 having passed through each of the ether layers.
9.  It is then run off into the beaker. 
10. The remaining aqueous layers continue to move through the funnels and eventually into the beaker as well.

When this sequence is finished, all the ether solutions have been washed five times with water, and all the water washes have been back-extracted as well. If the remaining ether layers are analyzed by TLC, it will likely be observed that reaction products are in funnels #1 through #3 or maybe #4.  Ether layers that contain products are pooled and can be processed further or dried and evaporated.  In general, NMR analysis of the crude material will not show any sign of residual DMF or DMSO after this treatment.

What is happening here is this: when the quenched mixture is initially extracted in funnel #1, most of the polar solvent goes into the water layer.  Some products and ether are also partitioned into the water, and some polar solvent remains in the first ether layer.  The aqueous layer moves into funnel #2 where it encounters fresh ether.  This extracts products out of the water, and it may also take up some polar solvent.  The process is repeated in each funnel.

But now consider the subsequent water washes.  When the organic layer in funnel #1 is washed with water, the residual polar solvent is extracted.  The actual amount of this polar material is relatively small since most of it went off with the first portion of water.  Thus, much less if any of the desired products are partitioned into the water.  This wash moves through the subsequent ether layers, removing polar solvent from each.  Each successive water wash moves polar solvent forward through the funnels, but as the amount of polar solvent in the earlier funnels drops the ability of each water layer to remove the desired product is reduced too.  The result is essentially an “elution” of the polar solvent with “retention” of the less-polar organic products in the earlier ether layers.

In general no more than five water washes are needed although in certain situations more may be required.

The process can be adapted to the use of solvents that are heavier than water as well.  If the extraction solvent is dichloromethane, the stationary phase becomes the water.  Funnel #1 is charged with the aqueous quenched mixture and dichloromethane, and smaller portions of water are put into funnels #2 through #5.  Dichloromethane portions are passed in sequence through the funnels and collected in the beaker having had the polar solvent washed out.

Modification for Working at Scale

The laboratory procedure described above would be unworkable at scale because too many vessels are required. The goal should be to retain the benefit of multiple extractions and multiple backwashes while reducing the vessels to just two. This could perhaps be modified by using one organic water-immiscible solvent denser than water and one that is less dense with a final combining of these two and recovery of the more volatile by fractional distillation. Using dichloromethane as the more dense liquid and isopropyl acetate as the less dense one the procedure might look as follows:

1. Dilute the organic reaction mixture with 1 part of isopropyl acetate and 3 parts water. 2. Stir and separate the lower water into a stirred tank.
3. Backwash the water with 1 part methylene chloride and return this to the mix with the isopropyl acetate in the reactor vessel.
4. Discard the water plus dipolar aprotic solvent from the holding tank.
5. Remove the methylene chloride by distillation from the reactor.
6. Add 3 parts of water to the residual isopropyl acetate containing the desired organic products and stir and settle.
7. Draw off the water containing the remaining dipolar aprotic solvent.
The products are retained in isopropyl acetate in the reactor.

Gas-Expanded Liquids as Solvents in Organic Synthesis

A gas-expanded liquid solvent combines a component that is a liquid at the operating temperature and pressure with a second component that is a gas under these same conditions but which is held within the liquid phase by the pressure used in the reaction and its solubility in the liquid component.

Amines as Gas-Expander for other Solvent Liquids

There are polar substances that are easily fluidized gases: ammonia, methylamine, ethylamine, trimethylamine, sulfur dioxide, and dinitrogen tetroxide being examples.  Some polar solutes may dissolve in rather apolar solvents, with the assistance of a minor quantity of such a polar fluidized gas. 

For such a co-solvent mixture to retain a fixed composition, however, the dissolution needs to be done well below the boiling point of the fluidized gas.  Then, heating the gas-solvent combination or placing it under a vacuum or a combination of these will remove the fluidized gas leaving the polar substrate in an essentially apolar solvent from which it is likely to crystallize readily.

Fluorinated compounds can be made to dissolve in hydrocarbon liquids in the presence of liquid carbon dioxide under pressure from which they crystallize out when the pressure is released and the carbon dioxide vaporizes away.

If the fluidized gas can be effectively recovered in usable purity and if by distillation the apolar co-solvent can be purified, then both solvent components can be recycled for a green process.

The most common co-solvent pair in the chemical literature is ethanol-water. Since neither ethanol nor water is a gas at ambient temperatures ethanol/water is not a gas expanded liquid. Methylamine/ethanol or ammonia/ethanol would be gas expanded liquids and could be useful at low temperatures. In the first instance, the methylamine might be recoverable by recondensation causing the crystallization to be from ethanol alone. Recovering ammonia on the other hand would be too expensive to be justified.

Ammonia is quite likely to be a satisfactory replacement for water in mixtures with other organic solvents such as ethyl acetate, isopropyl acetate, isopropanol, t-butyl alcohol, MTBE, acetonitrile, dimethoxymethane, THF, diethoxymethane, dioxane, nitromethane, nitroethane, isoamyl alcohol, ethylene glycol or DMSO and would constitute gas expanded solvents.  Ammonia may also work with solvents immiscible with water that require a polar additive to dissolve a substrate, such as toluene, hexane, heptane, cyclohexane, dibutyl ether, trifluoromethyl benzene, MTBE, and ethylene carbonate.

Sulfur Dioxide as Gas-Expanding Agent for Solvents

Sulfur dioxide, bp. -10 C, is readily condensed and has intriguing solvent properties. It is a Lewis acid, meaning it can accept an electron pair. It forms a stable complex with p-dioxane for example. It can be scrubbed by ethanolamine. Because it is a liquid denser than water, it likely can be used to increase the density of other solvents with which it is miscible perhaps even to the point where they may become the lower layer in a mixture with other organic solvents.

Dinitrogen Tetroxide as Gas-Expanding Agent for Solvents 

Dinitrogen tetroxide is another candidate for expanding the solvating properties of other solvents. 

Choosing the Scale for Laboratory Project Management Directed towards Chemical Process Development

Deciding the scale at which laboratory work should be done is a project management determination not a scientific one. The proper answer depends upon the physical resources of the laboratory, the budget for the particular project, the scale required to meet the final objective and the time available to meet that objective.

Whether the economic unit is a business or an educational institution the most frequent size at which synthesis experiments are performed can be quickly gauged by looking at the most common sizes of reaction glassware in the drawers of people working at the lab bench. For research conducted in schools, small scale work is more typical because the cost of chemicals is a substantial part of the overall expense. There the cost of student labor is low so using more labor is not a hardship for the professor. An addition consideration that reinforces this tendency is that academic research often works on targets that are many steps away from commercial starting materials. These target materials are time consuming to prepare and so the objects upon which publishable experimentation are conducted are precious and need to be hoarded.

On the other hand, in company laboratories, where the object is to produce either processes for manufacturing or families of compounds for property testing and where the wages of the scientists are a substantial part of the overall cost, the cost of the chemicals is a smaller proportion and working at larger scale saves project time and budget. Again, this will be reflected in the size of standard equipment found in the laboratory.

Although it is most convenient to work at the normal average scale set by the laboratory facilities this can be trumped by a particular project’s requirements so long as that is reflected in the project’s budget. Where this might be true, a discussion of the scale at which different parts of the work are to be performed should take place with the project manager to avoid later misunderstandings.

 http://chemjobber.blogspot.com/2011/11/process-wednesday-rb-woodward-on-scale.html

What is more, when the final objective is to produce hundreds or thousands of kilograms, even more risk related to scale up differences would be introduced if one starts working with only milligram quantities. Besides, if the cost of starting material is so high as to limit the scale of experimentation to the milligram range, it is also quite likely to be too high for commercial implementation at all. Another consideration is that developing a process step requires that many test samples be taken during the run to follow the reaction and to assess the qualities of the intermediates. A non-micro scale of operations is required to allow for representative and meaningful sampling.

What Size Steps for a Process Scale Up?

Why not simply jump from the scale at which a process step was developed to the scale at which it is planned to operate commercially?   Risk of catastrophic failure is the answer. The near optimal conditions for operating in laboratory equipment can still be quite different with respect to a number of variables from what must be done in a pilot plant. Just for starters, some parameters such as heating, cooling, stirring and the times for reagent additions cannot be physically matched on scale because of equipment limitations. Also other surprises can occur as one increases the size of operations and these can lead to product of unacceptable properties. Perhaps one ought to ask instead, “How well have I been able to scale-down the pilot   plant environment and reproduce it in my laboratory equipment."

 ‘Scaling down’ is the exercise of selecting the laboratory scale equipment that can best model operating conditions and provide data for mathematical models that successfully simulate pilot or production scale operations. Risk can be reduced by performing appropriate testing on such equipment.. If the experimentation has been conducted using exactly the same quality for solvents, reagents, processing aids and catalysts, the biggest source of deviation in scale up is removed. 

If the processing times including times of addition, times for transfer and times for filtration are approximately the same as will be used in the pilot plant, risk is reduced. 

If the corrosiveness and abrasiveness of the reactants have been tested upon the reactor construction materials this reduces another risk.

 If the procedure is insensitive to the agitation rate over a wide range another sensitivity has been allowed for.

 If the sensitivity to traces of air and moisture is known and taken into consideration life is simpler.

Easily Separated Water/Organic Solvent Systems for Reaction Between Organic Substrates and Inorganic Reagents

Aqueous acetonitrile and aqueous 1-propanol are two separate solvent systems that should be considered for reactions between organic substrates and inorganic reagents. To separate these reaction mixtures into two phases: an essentially aqueous one to extract the inorganic residuals, and the second to take up the organic products, T. Hori and T.Fujinaga [Talanta, 32, 8(2), 735-743, 1985] have developed a method that appears more practical than adding salts. This involves adding chloroform in the case of aqueous acetonitrile and cyclohexane in the case of aqueous 1-propanol. These additions of a third solvent component appear to be preferable to the usually large amount of a salt (impurities in which may cause undue contamination); also, the volume and composition of the organic phase can be predicted from phase diagrams and the overall composition of the solvent mixture. Volume-fraction diagrams are especially easy to use. Furthermore, equilibrium is attained in solvent mixtures more rapidly than in salting-out systems.

Reactions that require an aqueous-organic solvent are usually candidates for the application of phase transfer catalysis, and this should be the first option because of cost and waste destruction considerations.

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.

An ‘In Situ’ Source of Carbon Disulfide Reagent: An Otherwise Unsafe Chemical

Potassium ethyl xanthate

It is often the case that a process step is vetoed because a reagent or processing chemical is regarded as too risky. Occasionally, KiloMentor will try to identify such problem materials and suggest work arounds.

Some chemicals are regarded as too difficult to work with on scale and processes that require them are nearly always automatically rejected for scale-up. Carbon disulfide is in that category. This low boiling liquid has an auto-ignition temperature of 90 C and so broad a flammability envelope (1.3-50 Vol. % in air), that a fire is likely to result if a bit of CS₂ escapes from the process equipment and finds a  source of ignition, which can apparently be as innocuous as a steam leak. This point was made in the article, Holistic Route Selection, by Ronald B. Leng, Mark V.M. Emonds, Christopher T. Hamilton, and James W. Ringer,  Org. Process Res. & Dev. 2012, 16, 415-424. Nevertheless, these authors eventually stuck with advancing a process involving carbon disulfide reagent but only after adopting mitigation systems. To quote from the paper, “Ultimately a well-engineered CS₂ management system using returnable CS₂ containers, all-welded transfer lines, precise liquid metering, nitrogen blanketing, oxygen sensors, fugitive vapour sensors, and an automatic water deluge system were lines of defence that were incorporated into the process design…”
One lesson of this paper is that essentially any chemistry can be handle safely, if one is prepared to pay enough for the engineered system(s) needed to safeguard it. The problem is that unless the volume of the product is very high (their product was an agrochemical) and the profit margin good and stable, the up-front capital costs are likely to sink the project because of an inadequate discounted cash flow. Multipurpose plants simply cannot afford the required safety systems. It is not that the systems don’t exist.
This same paper points out that a large part of the risk using CS₂ occurs as much from when the material is being transported, stored, moved, measured as from the residue that remains in the waste streams.  The Dow Corporation developed a method of generating enough CS₂ to serve as a reagent ‘in situ’ which eliminated the risks from transporting, storing, moving, measuring and transferring reagent into the reactor. They did this by acidification of the solid salt, potassium ethyl xanthate which created carbon disulfide in situ. Using this sourcing, they obtained the same yield in the requisite transformation; however, they found that in order to completely consume their expensive intermediate substrate a slight excess of carbon disulfide was needed and this left some of it in the post-reaction mixture which gave issues in the subsequent centrifugation and gas venting system. This particular problem would not eliminate this approach for other process steps involving carbon disulfide reagent where an excess is unnecessary or when scrubbing of an excess can be simple.