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.

The Use of Azeotropes as Reaction Solvents

Constant boiling azeotropes are potential solvent systems for reactions.  Compared to any random solvent mixture, their advantage is that the composition can be consistently prepared with a stable ratio of components so long as the pressure can be held constant.  The mixture can be repurified at the end of its use, so long as the other components of the waste reaction mixture are not volatile, simply by distilling the residual solvent mixture.

Azeotropes are typically mixtures of quite unlike solvents so the combinations might be expected to show,  in most instances, substantially different properties from any pure liquid solvent.

What might some of these particularly attractive candidates be?

Acetic acid (58.5)         Chlorobenzene (41.5)  bp 114.7

Acetic acid (38.5)             Tetrachloroethylene (61.5)  bp 107.4

Acetone (88.5)      Carbon Tetrachloride (11.5)  bp 56.1

Carbon Disulfide (63.0) Ethyl formate (37.0)                  bp 39.4

Cyclohexane (72.0)         Nitromethane (28.0)          bp 70.2

Dibutylamine (49.5)        Water (50.5)           bp.97.0

Acetic acid/ chlorobenzene and acetic acid/tetrachloroethylene could be interesting solvents for free-radical reactions. both would also be more polar versions of chlorobenzene or tetrachloroethylene that would easily send all their organic solutes into the halogenated layer by simply adding water to the completed reaction mixture.

Acetone/carbon tetrachloride would be a less polar, lower dielectric constant version of acetone or methyl ethyl ketone.

Carbon disulfide/ethyl formate might turn out to be a more convenient fluid for working with compounds particularly soluble in carbon disulfide.

Cyclohexane/nitromethane probably has an upper critical solution temperature within a practically useful range. I the mixture can be cooled to give two separate phases this may be useful in separations.

The dibutyl amine/ water mixture will very likely be useful for dissolving more hydrophobic solutes into an aqueous phase.

It is frequently argued that single-component solvents are to be preferred over solvent mixtures because they are:

(1) easier to purify for reuse, and

(2) easier to acquire in precise, and pure form.

The first of objections is usually a 'red herring' as far as pharmaceutical or fine chemical synthesis is concerned. Solvents used to prepare such products are exceedingly rarely purified for reuse. The reason is simple; the analyses required to demonstrate that the recycled material is equivalent to fresh solvent are too costly and time-consuming.

The supposed second disadvantage simply would not be true for a lower boiling binary solvent azeotrope.

 

My Used Collection of Fieser & Fieser Reagents for Organic Synthesis for Sale

They have been sitting on my bookshelf pretty much unused since my retirement. They were certainly of great help throughout my career. Perhaps someone who is still in the lab would find them useful.

As the pictures show the first three volumes have been thoroughly used. The edges of the pages have yellowed and the hardcovers have been reinforced with transparent plastic tape complimented in the case of volume 1 by a strip of duct tape along the spine. All these are cosmetic, however, all volumes are firmly held together and completely readable.

Volumes 2 and 3 have my name SLEMON in green ink on the end of the stacked pages (see image). All volumes have personal dedications on the fly leaves. For example, the first volume was a 22nd birthday present from my parents; Volume 14th is signed going away present when I left my employment with Torcan Chemical Ltd., and Volume 16 was my 52nd birthday present. 

In total, the set weighs 40 lbs. This would need to be taken into consideration if they need to be shipped to a buyer.

Purchased new this set would cost about US$4,500. My interest is mainly to feel that the books are helping to continue to advance organic chemical synthesis. I would be happy to pass them on for US$3000 so long as I know they will be finding a good home! 

I cannot count the nights I jumped out of my bed with an idea and ran to my volumes to check out its feasibility in greater explicitness.

If a reader is interested in this offer, I can be contacted at clarkeslemon@gmail.com.

These are still available as of November 1st 2025.

 

What Might Break the Miscibility of Tetrahydrofuran and Water

 

Tetrahydrofuran and water when mixed together form a single-phase whatever their relative proportions. Diethyl ether, which has two more hydrogens per molecule, forms two distinct phases when mixed with water. 2-Methyltetrahydrofuran forms two layers as well. Methyl ethyl ketone with the same molecular formula forms two layers. 

Among four carbon alcohols, 1-butanol is only soluble between 6 and 9% by weight at 25℃. 2-Butanol is only soluble about 18% by weight at 25℃. 2-Methylpropanol is only soluble about  7-8% by weight at 25℃.

Therefore, each of these can be called immiscible with water; however, t-butanol with the same molecular formula is completely miscible with water.

Clearly at four carbons and one oxygen in a molecular formula we are getting close to some discontinuity in mixtures with water.

This is more than just curious. It is important because reactions conducted in these solvents are often quenched and worked up by adding water and it makes a difference whether they form one or two separate fluid layers.

The situation with regard to THF is particularly important because organolithium and Grignard reagents are so often necessarily or most often prepared in this solvent. 

It is of considerable consequence that THF does not provide any azeotrope that can be used to dry THF.

A mixture of 18 grams of water and 64 grams of THF would contain 1 mole of each molecule. Here is my question: What is the smallest weight of any other common solvent that, added to this mixture, would give a clean interface between two distinct layers, and what is that third solvent?  I do not have the answer. But the answer has a practical importance because such an addition would provide one simple element of a work-up for a reaction conducted in THF and quenched with water.

For simplicity and to inspire imaginative thinking I have chosen the moles of water and THF to be 1:1. My guess would be 2-methyl propanol.  It is apparently poorly solvated by water alone but it would provide a hydrogen bond to donate to the electron pairs of THF. Another promising candidate would be t-butanol. If t-butanol caused separation into two discrete phases it would be truly remarkable since all three solvents are miscible as binary pairs! However, the hydrogen-bonded complex between a t-butanol molecule and a THF molecule might mutually satisfy their polarity needs and present a hydrophobic exterior to the water.

If I had a third guess, I would add a carbon and try 1-methyl-2-butanol (t-amyl alcohol). That would preserve the same hydrogen bonding but increase the overall hydrophobicity of any binary complex. t-Amyl alcohol has only an 11% solubility in water at 25℃.

I wish someone would do this last experiment:18 grams of water, 64 grams of THF, then add slowly t-amyl alcohol with stirring until 78 grams of the alcohol were added. Do the layers separate?