Isopropyl Alcohol/ Toluene/ Water: A Thermomorphic Ternary Azeotrope for Extractive Purification

 

There are several references to this Ternary System: Isopropyl Alcohol, Toluene, and Water at 25°C.

E. Roger Washburn and Albert E. Beguin, J. Am. Chem. Soc. 1940, 62, 3, 579–581; J. Am. Chem. Soc. 61,1694 (1939); 54, 4217 (1932); 56, 361 (1934)

It is well established that isopropyl alcohol, toluene, and water mixtures upon distillation pass over into the distillate as a tertiary azeotrope that boils at 76.3 C and has the weight composition 38.2% IPA, 48.7% toluene and 13.1% water. When it separates into two liquid phases the upper layer is 92% by volume and the lower 8% by volume. The composition of the upper layer is 38.2% IPA, 53.3% toluene and 8.5% water and has specific gravity 0.845. By contrast the small lower layers 38.0% IPA1.0% toluene and 61.0% water has specific gravity 0.930. This behaviour of splitting into two layers on cooling is called thermomorphic.

What is not apparent from my examination of what literature I can access is the temperature at which these two phases merge into a single phase. That is: What is this mixture’s upper critical solution temperature (UCST)?

To be useful in the application I am contemplating there needs to be a manageable difference between the lowest temperature needed to get a homogeneous solution and the azeotropic boiling temperature. That is, specifically the UCST needs to be less than say 50 C.

My idea is to use portions of the lower phase of the separated ternary azeotropic composition (with a composition of 38.0% isopropanol, 1.0% toluene and 61.0% water)  in the volume proportion of 8 volume % versus the 92 volume % of the upper phase to sequentially wash the upper toluene rich phase, so as to remove somewhat preferentially more polar constituents from a mixture of substrates initially dissolved in the homogeneous single phase ternary azeotropic combination of isopropyl, toluene and water.

This, it is hoped, will produce a result similarly to what is called ‘swish’ trituration. In ‘swish’ trituration a solid mixture of substrates is repeatedly triturated with an anti-solvent in which the predominant component is very nearly completely insoluble but in which the impurities are meagerly soluble. Even so, they are removed because of the substantial quantities of the triturant used. If this were to work, the result would be the purification of the main component.

This is how I imagine the process would be executed.

Experimental

10 liters of the IPA, toluene, water tertiary azeotrope are prepared. The mixture is heated to a temperature conveniently above the UCST and divided into two portions, one of about 1 liter and the second about 9 liters. The 9 latter portion is allowed to cool below its UCST and the lower more polar phase separated and stored in a stoppered vessel. This phase labelled (A) will provide the multiple wash portions used to remove more-polar components of the mixture of substrates. In a separatory funnel, part of the 1 liter portion of the still warm, still a single phase tertiary azeotrope which we call (B) is used to dissolve the mixture of substrates to be separated. For about 2 grams of mixture, 100 ml of warm homogenous azeotrope is used. The test mixture must dissolve completely at the warm temperature where there is just one liquid phase and when the solution cools it is necessary that two liquid phases separate. 

It is essential that two liquid phases form even though the presence of the charge of substrates is included. It is for this reason that I am choosing to only use 2% weight to volume (substrates to solvent). If two phases do not separate, it will be necessary to increase the amount of azeotrope solvent mixture until they do. On the other hand, for reasons of the throughput of the purification, it is desirable to use as large an amount of substrate mixture as is consistent with retaining two separating liquid layers.

When the liquid in the separatory funnel has cooled to room temperature, remove the smaller volume of the lower phase into a graduated cylinder and note the volume of this phase. Transfer this, what I will call the 1st wash, to an erlenmeyer flask and save it for analysis to learn the degree to which you have concentrated the polar impurities in this 1st wash.

Now, into the separatory funnel add the exact same volume of  (A) as you have removed in the first cut. Two phases should be present since what you are adding is pretty close in solvent composition as what has been removed. Warming in the separatory funnel to above the UCST will produce one phase and cooling back will split the volume into two again. The substrates, which we seek to separate, will have again partitioned between the layers. Cut again and move that layer into a second erlenmeyer flask for analysis.

How successful the technique is for purifying a major less-polar substance will depend upon the substance being substantially more soluble in the toluene-rich layer than in the water-rich layer. The more polar impurities need not be particularly soluble in the water-rich phase so long as they are more soluble than the major component. Poorer solubility of the polar impurities only means a larger number of these small volume washes will be required. Note that the size of the washes must be the same as the volume of the first lower layer. If not the composition of the ternary azeotrope in the separators funnel will change too much and the layers may no longer separate properly. 

An advantage of working at-scale in a closed inverted reactor as the separatory vessel is that a separation temperature as low as -20 C can be used because extraneous water from the plant air cannot be condensed into the liquid medium from the air— the liquid layers are covered by inert gas!

Dissociative Leaching for Simple Large Scale Purification

 

Dissociative leaching separations are a subset of dissociative extractions. Sometimes, the ionizable substances to be separated are both not significantly soluble in an aqueous medium. If the more reactive species (more acidic or more basic) forms the more water-soluble salt upon reacting with an insufficiency of salt former while the less reactive constituent remains insoluble in the water then excellent separations can be achieved simply by leaching the crude mixture with an aqueous solution of the less than stoichiometric reagent and filtering the residual solid from the aqueous liquid. The more reactive component is isolated from the aqueous phase and the less reactive material from the solid on the filter. 

For example, the separation of a mixture of o-chlorobenzoic acid and p-chlorobenzoic acid is carried out by suspending the solid mixture in an aqueous solution containing just enough sodium hydroxide to neutralize the ortho isomer. The separation factor was as high as 26. At 65 C the o-isomer was leached out completely from a mixture initially containing 40% o-isomer. Higher solubility coupled with a lower pKa of o-isomer is responsible for such excellent separation.

The Most Common Visitors to KiloMentor

 

Persons from the United States are by far the majority of visitors to the KiloMentor Blog. They exceed the visitors from the next most prominent country, India, by a factor of 5-6. After that come Britain, Canada, Ukraine, Russia, China ( listed as an unknown country) and Germany.  The unexpected one of these is Ukraine.

The Russian visitations are probably automated robotics since the number of individual contacts is a regularly large but exact number.

Magnesia Adsorbent for Removing Olefinic or Aromatic or Coloured Impurities from a Reaction Mixture

 Even a chemistry undergraduate is familiar with the use of carbon powders for decolourizing solutions of organic compounds during recrystallization from organic solvents. However, charcoaling for decolourizing has some serious shortcomings when contemplated for application at scale. [Neal G.Anderson, Practical Process Research & Development Academic Press 2000, pg. 17-18]. 

For a very long time, it has been known that magnesia strongly adsorbs unsaturated and aromatic compounds while having less affinity for oxygen-containing functional groups such as carbonyls and ethers [L.R. Snyder, Water Deactivated Magnesia as a Chromatographic Adsorbant,  J. Chromatog., 28 (1967) 300-316.] Indeed so strong is this binding if the magnesia is not deactivated with small amounts of water, that chemisorption of polyaromatics can occur and these materials cannot be liberated without destruction of the adsorbent. These chemisorbed substances can often be eluted with water-wet organic solvents.

 
 Coloured impurities very often are polyunsaturated or polyaromatic materials. In removing these coloured impurities from a less unsaturated material there is no concern whether the coloured impurities become strongly adsorbed or chemisorbed so long as they are retained sufficiently tightly to the solid so that passing a solution of the desired compound with its coloured impurities through a plug of magnesia traps the colour and the filtrate contains the desired material, now colourless.

One would think that magnesia adsorption could also be used to remove even colourless contaminants in a reaction mixture so long as they were significantly aromatic or olefinic and the desired substance was not.  

A History and Philosophic Approach of the KiloMentor Blog

 

This is a reprint of the first blog article on this site. In retrospect, I think the original purpose has been served, yet many of my readers may not have properly understood the perspective.

 In 2006, I started a blog called ’KiloMentor’. The goal was to provide training and updating in the methods for chemical process development emphasizing scale-up of organic synthesis, particularly scale-up of high-value pharmaceutical products. I recognized that there were textbooks, symposia, and courses for this purpose but they were expensive and not equally available in different places in the world.

 

Moreover, in academia, the treatment of chemical process development was neither widespread nor generally thorough. The KiloMentor blog was free and available wherever access to the worldwide web was possible. My blog was originally hosted at a site called Chemical Blogs. Later the articles were transferred to a different, dedicated site. A few years ago this site was shut down when I did not pay for the web address. This Google blog will be a republication and supplementation of those articles.

Below is a revision of one of the earliest articles from the original KiloMentor archives. The original was written in 2007.  This article restates for new readers the core idea of the Kilomentor process development philosophy and offers an approach that I think leads consistently to valuable considerations, if not complete solutions. 

In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, for example in building a house, we handle the pieces, we position the pieces, and we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: too small to touch, to align, or even to see. 

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. then the chemist presents the proposed reaction partners to each other under the orchestrated conditions and they interact, as their nature dictates, but hopefully this is also as we have planned.  How is this perspective different from the conventional one?  Chemical process development is simply efficiently making these parameter choices that cause nature’s choice to comply with what we want the outcome to be. Nature- to be commanded, must be obeyed.

Separation as the Focus of Chemical Process Development 

According to the academic, synthetic chemistry tradition, synthetic accomplishments are judged on the basis of the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts, and other excipients are in the background (the attitude is that it can be done and will be done BUT these are not pertinent criteria to evaluate the quality of the synthesis).  The giveaway phrase of those who harbor this philosophy is “the product was isolated in the usual way.”

From the KiloMentor perspective, in this age of online substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computers alone anymore. Now it is creative ideas for separation and purification that are not easy to search that have become the art element of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity has become paramount. 

Is there any particular value in this way of looking at the process rather than the traditional way which was focusing on the series of chemical reactions and taking the separation of intermediates as obvious, merely technical, work?

 My perspective rather emphasizes: 

• The work involved setting up and controlling the necessary reaction conditions. 
• The work involved quenching the reaction condition/then working up the reaction and finally isolating the desired product. 

The value in this KiloMentor perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction phase, while A & B are reacting with each other, is minuscule compared to the money, manpower, and resources expended preparing for the reaction and recovering pure product from the reaction.

The clash of these perspectives can be focussed by the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel, crystallized or distilled to give a practical purity intermediate adequate to use directly in the next step". 

People have personal preferences and this is as it should be in a pluralistic society. Still, I pick the second sequence and as the need for larger quantities and higher quality intensifies, I increasingly prefer the second route. 

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield or the yield in individual steps does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy, and scalability. 

OK, so what. How does this insight change our behavior in the synthetic laboratory, office, or library? 

Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation are proposed as a quantitative tool to rank the challenges of a process scale-up.

We should evaluate or rate synthetic schemes using more criteria:

1.   Number of Chemical Steps 

2.   Isolated overall Yield 

3.   Yields of the Individual Steps 

4.   Difficulty Rating for Each Reaction Mixture Separation

5.   Number of ‘Phase Switches’ in the Synthetic Process

6.   Intermediates that are Acids or Bases

7.   Ease or Difficulty in reaching Practical Purity

How could we execute these ratings? We could classify work-ups. 

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. The product can be separated by crystallization or precipitation as a filterable solid.

C. Product can be separated by atmospheric or vacuum distillation assessed from an approximated difference in boiling points (based on molecular weights)

D. The product can be separated based on chemical reactivity (formation of a reversible, simply separable, derivative, or destruction of a contaminant by reaction)

E. The previously unknown product must be crystallized to free from unknown impurities

F. The product seems likely only to be separable in practical purity by chromatography.

Clearly, as process chemists, we want to face more A-C separations and fewer D-F type separations.

 ‘KiloMentor’ articles will offer up particular tactical tools that fit into its distinctive strategy of pharmaceutical or chemical process development. It will also review considerations particularly important for plant-scale processing as contrasted with laboratory-scale syntheses.