Why Use a Miscible Solvent Mixture?

Throughput

A solvent mixture may well dissolve more substrate than pure solvent. In fine chemicals synthesis where solvent is not recycled but sent for destruction there is no cost advantage from a single solvent but getting more substrate dissolved homogeneously in a reactor can improve the economics by increasing throughput, especially in early process steps which need to be run multiple times.

Increasing the Heat Capacity

The preferred solvent for yield optimization may be one that boils well above the best reaction temperature. Adding a co-solvent that boils at the desired reaction temperature can increase the heat capacity of the medium at the reaction temperature because the lower boiler’s vaporization into the condenser and the returning condensate will cool the reactor. Consequently, addition rates of reactants can be higher.

Changing a Phase’s Density

Some solvents are more dense, some less dense than water.  In work-ups with water, sometimes having the product containing liquid phase more and sometimes less dense than water has advantages. The number of large vessels needed to execute a process step may depend upon it. Fewer vessels mean less cleaning and a smaller burden on plant facilities.

Reducing the Solubility of a Product or Co-product

Decreasing the solubility of a product or co-product can cause it to precipitate as the reaction proceeds. This can drive an equilibrium towards completion and raise the overall yield.

Making Telescoping Reactions Easier

Sometimes it is not useful to isolate a process intermediate but the solvents appropriate for the present and subsequent process steps are not the same. A solvent switch is required. Evaporation to dryness is not possible at scale. It would be advantageous if the second step in the telescoped pair was optimized in a solvent mixture consisting of a minor amount of the first solvent and a majority of second solvent. If this were done it would not be required to substantially remove the first solvent. This might save substantial time.

Because the Solvent Mixture Selected is a Constant Boiling Azeotrope

A constant boiling azeotrope has a fixed composition and it boils at a constant boiling point. In these respects, it is the same as a pure single molecular species. It can usually be purified by simple distillation. However, many azeotropes have the advantage that by changing the pressure-usually by reducing the pressure- the azeotrope can be split into its component substances by distillation. This distillation at a different pressure can potentially remove the better solvent and lead to precipitation or crystallization of a solute.  

To Reduce Solvent Viscosity

Solvents that are viscous are often usefully high boiling but their viscosity is a problem for stirring and for heat conduction. Mixing with another solvent can reduce the viscosity of the reaction medium.

To Provide a Distillation Chaser

Adding a higher boiling solvent into a reaction solvent mixture ca provide a chaser for reaction mixtures that are subsequently worked-up by distillation. Sometimes a substantial amount of product is lost in the still pot and the distillation column. Of course, this chaser can also be added after the reaction is over but before the distillation step.

Drying Simplicity 

Drying solvents on scale with inorganic salts followed by filtration of the inorganic salt hydrates uses labour, equipment, and time inefficiently.  It is greatly disfavoured for work at scale. The preferred method for solvent drying selects a solvent that forms an azeotrope with water and distills a portion of the solvent as the azeotrope.

Raising the Freezing Point 

At what temperature does the solvent that is being considered solidify or become highly viscous? The freezing point can limit the range of temperatures that can be used in the optimization.  Lowering the temperature is often the best option for increasing the selectivity of a desired reaction versus competing reactions that produce by-products. If low temperatures create viscous reaction mixtures, these can result in hot-spots during reagent additions, inadequate mixing leading to incorrect stoichiometry, creating in turn by-products, and poor crystallization control. For example, DMSO when diluted with a small amount of toluene is more resistant to freezing and so can be cooled to a lower reaction temperature.

Removing Triphenylphosphine Oxide Byproduct or Coproduct from a Reaction Mixture

Triphenylphosphine oxide is a common and annoying coproduct in the Wittig reaction, for example. Many ways have been proposed for the separation of this contaminant but most are not fast, cheap, rugged, or necessarily quantitative. It is known that triphenylphosphine oxide forms large blockish cocrystals with N-acetylglycine with a very strong hydrogen bond between amide and phosphine oxide. It can be imagined that these adducts further associate as dimers through the free carboxyl group producing an even high molecular weight dimeric adduct. Perhaps the addition of excess N-acetyl glycine into a solution of desired product and triphenylphosphine oxide impurity could precipitate the cocystals and perhaps residual N-acetyl glycine. This has not been established. But, if it works filtration would give a purified solution of the desired product with just some residual dissolved N-acetyl glycine and so long as the desired product is not acidic, this residual N-acetylglycine will be cleanly back extract  into aqueous base.

A Trick for Working Up Reaction Mixtures Comprising Polar, Water-Soluble Organic Solvents

Suppose you have a neutral substrate contained in a polar organic solvent and would like to wash it with water to remove some reagent byproducts, but that solvent is miscible with water? Examples would be DMF, DMSO, THF, Dioxane, Isopropanol. Consider adding the water first to give a single phase, but then, into this mixture of the first two, add methyl acetate or ethyl formate. These lower esters are not particularly soluble in water so what will happen when it goes into this mixture? Most likely, two phases will separate; an organic phase comprising mostly the troublesome polar organic solvent ( ie DMF, DMSO, THF, Dioxane, Isopropanol ) along with the lower ester and a second phase which is predominantly water. Your organic reaction product will be substantially in the combined organic layer. A cut can be made.

This procedure is deemed to have the advantage that the two phases initially form as small droplets ensuring good contact between the phases. In regular extractions wherein the two immiscible liquids are mixed from bulk, in slow mass-transfer systems, high-intensity mixing is required. Such intense mixing can form fine dispersions which reduce the coalescence rate or, in the presence of surface-active impurities, may even cause a “stable emulsion”. This is one of the operating hazards of solvent extraction equipment. This order of mixing: the two miscible solvents first followed by the third which causes the phase separation is taught in US 5,628,905. Quoting from this publication, “The inherent advantage of this method is that it works effectively even in the presence of substances (solid or dispersed) that cause the formation of emulsions or stable dispersions.”

Distillation of this mixture should drive off the low molecular weight ester that was added as a processing chemical leaving the original organic solvent separated and washed clean!

Organic solvents such as ethyl acetate can be freed from small amounts of DMSO by washing with 5% sodium chloride in water. This trick was taught to me in 1997 by Jong Tao, then of Torcan Chemical Ltd..

A Novel and Possibly Versatile Method for Separating of Aldehydes Alone

For 40 years I have been thinking about commenting on this article published in the Chemical and Pharmaceutical Bulletin in 1980. In that year Shunsaku Ohta and Masao Okamoto published a three-page communication that taught a simple method for extracting only aldehydes into an aqueous layer and then recovering them in pure form and high yield. I expected to find more complete details later along with experimentation to support a hypothesis for the mechanism of action and I expected many subsequent applications of the method. Nothing could be further from reality. There does not seem to have been any further work or use!

What the authors taught in Chem. Pharm. Bull. 28(6) 1917-1919 (1980) was that a 1.2 M 6-aminohexanoic acid sodium salt solution could quantitatively carry aldehydes, from mixtures of substances comprising at least one aldehyde dissolved in either diethyl ether or diisopropyl ether, into an aqueous phase. Then, after separating the aqueous and organic solvent layers, the aldehyde could be liberated by acidifying the aqueous phase to pH 4-6 and back extraction into an organic phase….. free of non-aldehydes (including ketones). 

6-aminocaproic acid (6-aminohexanoic acid) is cheap. It is the monomer for making nylon! 

The data in this communication shows that the method is not completely selective for aldehydes. Cyclopentanone was partly selected by the reagent, even though cyclohexanone was completely excluded.  Aliphatic aldehydes gave emulsions but these were cleared by adding some isopropanol.

So this procedure seems very practical. Of course, it may not work! Perhaps that is why nothing more has been written about it. But surely it is worth investigating further.

The authors pictured the isolation as proceeding through the formation of the imine, the covalent bond of which pulled the aldehydic moiety into water courtesy of the sodium carboxylate functionality on the other end of the reagent. The authors do not offer any explanation, however, of why the equilibrium so greatly favors the imine. 

Also left hanging- how high can the molecular weight of the aldehyde be and still have it successfully transferred to the aqueous phase? What organic solvents can be used besides diethyl ether or diisopropyl ether? All remains clouded.

Interview Questions for Testing Synthetic Organic Chemistry Technical Expertise

About the Nature of the Test

One objective of these questions is to provide recruiters who are looking for new employees who must have organic synthetic chemistry laboratory skills, quick access to questions pertinent to real laboratory skills and know-how. 

Questions target what employers might ideally wish candidates to already know when starting employment. The recruiter can either select questions that most closely reflect the anticipated work area or select questions at random to be sure that the candidate has not selectively prepped for the interview. It is not expected that any candidate will be able to answer all these questions. 

More questions are provided than any candidate could be asked or would have time to answer. This is so that a candidate cannot memorize answers to just a few specific questions and so falsely convey that his/her knowledge is more comprehensive. 

Sadly, resumes can no longer be taken as properly truthful. False claims are common; some verification of knowledge and experience is essential and testing needs to be rapid-fire.

Although your own questioning will always remain the most pertinent, supplementing with some of those proposed below can broaden the basis for what is a heavy responsibility.

This blog article has a second purpose. These same questions can guide prospective employees towards the entire range of skills and know-how that perhaps is being sought.  Candidates can use the questions to broaden their job preparation. Answers or partial answers can be found by searching keywords with Google narrowing answers down in many cases by including the keyword KiloMentor in their search or by searching using the search tool in the KiloMentor blog itself.

Questions are selected not only to elicit particular information but also to initiate a technical conversation between the interviewer and the candidate. Sometimes questions assess how a candidate reasons from what is provided.

Candidates are well advised to immediately acknowledge to the interviewer that they really aren’t confident about some questions.  This will save time and provide the interviewer with more time for you to show your strengths.

Questions are targeted towards preparative organic synthesis, not analytical work. Although there exist preparative variations of analytical methods, ie preparative HPLC, and preparative GC, these are never the answers sought here. When one is asked about useful methodologies they most often relate to rugged scaleable methods. The questions range between simple and very difficult. Unambiguous communication of subtle distinctions relating to science is an important skill for working in teams. If you believe that more information is needed for an answer, specify what is needed, how you would obtain it, and why you consider it essential for the answer.

Test Questions

Concerning fractional distillation, what is a 'pig'?

In words or a sketch, describe a kugelrohr assembly.

What is the meaning of 'star', concerning a round-bottomed flask?

With the assistance of a simple diagram, show what is meant by 'R_f' in thin-layer chromatography?

Put the following solvents in approximate order of the Eluotropic series, ending with water: acetone, benzene, carbon tetrachloride, chloroform, cyclohexane, dichloromethane, diethyl ether, ethanol, ethyl acetate, hexane, methanol, n-propanol, toluene, trichloroethylene, water. What factor most influences this series's order?

What does 'quarantine' mean in the context of process validation and chemical processing?

What is the difference between 'reprocessing' and 'reworking' concerning process validation?

What is 'inverted filtration'? When is it used? How could you prepare such a filter for laboratory-scale use from common laboratory equipment and materials?

Why is it important in 'fractional distillation' to have the fractionating column precisely vertical for the best results?

What is an 'unimolecular reaction'?

For a bimolecular reaction, what decrease in reactor volume would be predicted to give a doubling of the reaction rate?

As part of a separation, you have immobilized a substance that contains both a primary amine functional group and a carboxyl functional group on a cationic exchange resin in the protic form. What solvent systems would you contemplate for eluting this substance?  Put another way what properties should this elution solvent have?

Explain what 'lyophilization' is.

What very pragmatic advantage would lyophilization have over stripping solvent on a rotary evaporator?

'Inverted filtration' refers to which of the following:

1. A chemical operation where a slurry is applied to a filter surface through the stem of the filter.
2. Filtration of a reaction mixture before beginning the reaction.
3. Filtration of a partially charged reaction mixture, before starting a reaction, to obtain a purer solid product at the end.
4. Filtration using a filter stick.
5. Filtration by the application of pressure rather than vacuum.

A 'unimolecular reaction' is:

1. Another term for a rearrangement
2. A reaction such as 1A + 1B giving 1 A-B in which all the coefficients are 1.
3. A reaction performed using one mole of substrate
4. A reaction in which the rate is directly proportional to the substrate only.

Name two reagents for destructive visualization of spots on silica TLC plates?

If you spill mercury metal on the floor, what methods could you practically use to clean it up?

Draw an equipment setup for doing steam distillation at a lab scale? What kinds of compounds is it used to separate?

What characteristics of components of a mixture should suggest steam distillation as a possible treatment?

What is the temperature of the steam in a steam distillation?

You have a hexane solution that contains your crude product dissolved in it but the solution is black in colour. The chemical structure of your target product does not have any strong chromophore nor does it contain a metal. Propose 4 or 5 suggestions that might remove the color or substantially reduce the color's intensity.

You need to find out how to identify spots on a TLC plate containing a particular functional group. Where would you look to find an appropriate visualizing agent? Alternatively, what search terms would you use to search for this information so that you would end up with only a few good answers?

How could one quickly, without entering the laboratory, identify a reaction that is likely to be highly exothermic from its balanced chemical equation?

You are trying to dry an organic solid in a drying oven, but its weight does not seem to level off. What might be happening?

You have freeze-dried a solution containing a polar organic solute and some inorganic sulfate salts. What method would you try to easily separate the organic solute from the sulfate salts?

Draw the structure or provide the trivial name for a reagent that can be used to separate

1. Aldehydes or ketones from non-carbonyl compounds
2. Aldehydes from ketones
3. Aldehydes or methyl ketones from other carbonyls

Name three functional groups that could be present in an organic molecule of five carbon atoms that is insoluble in concentrated sulfuric acid?

Finely divided anhydrous calcium chloride when stirred in hexanes with a drop of ethanol as a catalyst will often form solid complexes with compounds containing what functional group?

What reagent reacts reversibly with both methyl ketones and aldehydes to give derivatives that are often water-insoluble?

What is the Hinsberg test? What classes of functionality does it distinguish between and how is each functional group sub-type distinguished?

Do you know a reagent that reacts as a Hinsberg reagent but allows the original functionality to be regenerated?

If a compound that you wish to purify has too high a boiling point to be conveniently distilled, what common derivative class should you consider making to lower its boiling point?

In distillation, what is a chaser?

In distillation, what is a boiling chip?

List ways to prevent bumping during vacuum distillation.

What is the difference between evaporative /molecular distillation and regular fractional distillation?

When a high boiling oily organic is distilled from one glass bulb into an adjoining glass bulb using a mechanical device that simultaneously applies vacuum and rocks the bulbs, what is the apparatus called? Why is the apparatus rocked back and forth?

What is the chemical structure of the functional group called oxime?

What solid derivatives of alkynes do you know?

You are conducting a reaction in which reagent A is mixed with substrate B at 50°C in a variety of solvents. The reaction mixture consistently becomes black and a tar is formed. What kinds of changes might you make to improve the situation? Give reasons for your plans. Make your answers as generally applicable as possible. If you make assumptions say what these are.

What are the simple things one should do if one is planning to scale up a transformation that might be exothermic?

Neal G. Anderson, in his book, Practical Process Research & Development, particularly suggests avoiding as much as possible changes in the oxidation states of the process substrate. What reasons would there be for this advice?

During the workup of a reaction, you are faced with an emulsion between a toluene solution and a dilute aqueous solution. The reaction is one element of a process scale-up. What methods can be used to break the emulsion? If you are already in the plant what methods are more preferred and why?

What is a “kill solution” in the context of chemical process development?

Which of the following solvents would be problematic for use at scale in a chemical plant setting?
pentane, heptane, carbon disulfide, diethyl ether, methyl t-butyl ether, diisopropyl ether, di-n-butyl ether, benzene, N, N-dimethylaniline, carbon tetrachloride, toluene, chloroform, isopropyl acetate, 2-methoxy ethanol, HMPA, ethylene glycol

What is a thermomorphic solvent?

What is the special difficulty in switching from one solvent to another as part of a reaction step in plant or pilot-plant equipment that is no problem when working at a laboratory scale?

Propose a process sequence for switching from dimethylformamide solvent to methylene chloride without a water drown-out?

Describe solid-liquid extraction. What are its advantages? Give examples of its use for functional group separations.

How does dry column chromatography differ from regular chromatography? What would be some of the advantages of this technique for separating small quantities of pure compounds?

You want to separate two substances in which the most prominent difference between them is that one compound contains an aromatic ring while the other does not. What chromatographic adsorbents would be the best candidates for the separation? Do not just propose any adsorbent with low loadings and long columns.

You have been given a written procedure for a chemical transformation that works in high yield and good recovery. The problem is that when this is scaled up in the available reactor, not enough material can be produced. What do you do to improve the throughput? What problems are likely to arise when you try the solution?

What are scavenger resins? Give an example of the use of one.

Separation of a few milligrams of pure compound is being tried on an analytical HPLC column using analytical separation conditions but as the injection size is increased the detector shows peaks quickly overlapping. Can anything be done?

For what is AgNO3 on silica gel used in the laboratory? 

What is co-distillation? Why would one use this technique?

You have a thermally stable but almost insoluble compound that is not adequately pure. The desired compound is the main component. Product and impurities can be separated analytically by TLC on silica gel, but only after multiple elutions because the Rfs are almost zero. How can the chromatography apparatus be changed to facilitate in the laboratory the separation using a reasonable volume of solvent?

You need to know how to identify the spots on a TLC plate. Where would you look to find an appropriate visualizing agent? On-line what keywords would you use? 

Do you have experience doing substructure searching in chemical databases?

What is Claisen’s alkali? What is its most important use?

What is a more efficient way than washing with water to remove traces of pyridine from a diethyl ether solution?

If a multifunctional compound that you wish to purify has too high a boiling point to be practically distilled, what common derivatizing agent should you think of to lower the boiling point?

In chemistry what is a ‘chaser’?

What is extractive distillation? What kind of separation problem is it helpful with?

What is the difference between evaporative/molecular and fractional distillation?

What is ‘phase switching’ in chemistry?

You have equal volumes of pyridine and water mixed together; is there a simple way to achieve rough phase separation to recover most of the pyridine?

One way to separate compounds with alcohol functional groups from compounds that are not alcohols by extraction is to prepare an alcohol derivative which can be extracted into an aqueous phase and then subsequently reform/reconstitute the alcohol. Describe methods for separating alcohols from non-alcohol by way of extractable and reversible derivatives.

Suppose you are asked to resolve the compound 1-phenyl-1-(2’-bromophenyl)prop-1-yn-1-ol.

First, What is the structural formula of this compound? Second, what actions would you take to as expeditiously as possible, carry out the resolution?

Reactive Distillation using Enamine Formation for Separating Different Ketones also useful for Separating Ketones from non-Ketones

Two ketones with different steric surroundings, when caused to react with an insufficient quantity of an appropriately selected cyclic secondary amine, will have different rates of formation and different equilibrium concentrations of enamines.

For example, according to Peter W. Hickmott in Tetrahedron 38, 1975 (1982), a mixture of non-, mono-, and di-methylated 4-t-butyl-cyclohexanone was separated by first allowing the mixture of ketones in refluxing benzene to react with gradually increasing amounts of morpholine until gas chromatographic analysis indicated that all of the non-methylated fraction had disappeared owing to the formation of its examine. Then the unreacted ketones were removed and treated with increasing amounts of the more reactive amine pyrrolidine until gas chromatography show all of the monomethylated compounds had disappeared by forming enamines. The dimethylated ketone could then be distilled off and separation was complete!

A small steric or molecular weight difference is magnified into something that allows simple separation.

It should be obvious that the same methodology in a simpler form could be applied to separating a mixture of ketones and non-ketones. The ketone fraction would be derivatized with an appropriately reactive cyclic secondary amine, the catalyst neutralized and the fraction (not changed in properties) separated. The ketone fraction could be converted back from enamine by acid-catalyzed hydrolysis and the secondary amine taken into acidic water.

Recovering High Boiling Dipolar Solvents Miscible with Water for Recycling or Disposal At-Scale

Kilomentor has written blog articles covering the methodology in US 5628906 called Extraction Process that is particularly useful for working up reaction mixtures that contain suspended solids. These teachings are also applicable to simple, potentially lower cost recovery of high boiling organic solvents that are contaminated with large proportions of water.

Aqueous Drown Out Work Ups

Very often the simplest isolation of product from reactions in such solvents is a drown-out done by pumping the organic reaction solution into large volume of ice-cold water or water mixed with ice. This action where it works well precipitates the product which can be recovered from the mostly aqueous slurry. This has been done with dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, sulfolane, and triglyme to name a few. 

After filtering off the desired precipitated solid operators are left with a homogeneous liquid comprising perhaps 80% water and 20% higher boiling organic solvent. This cannot legally be discharged into a sanitary sewer and would be expensive to send for destruction. Suppose instead we recharge this liquid (let us as an example say it is 80% dimethylformamide and 20% water) into the cold reactor from which the slurry just came. Suppose we then add what is called in US 5628906 a ‘secondary solvent’ ( let us, for example, use 1-butanol) in whatever, preferably minimal, volume that will cause the reactor contents to split into two phases; one predominantly water and the other, a mixture of the problematic high boiling water-miscible solvent (such as dimethylformamide from TABLE I in the patent ) and say 1-butanol (from TABLE II in the patent). Now we can cut the predominantly water phase and send it alone for waste. The mixture of 1-butanol and DMF, the primary and secondary solvents of the invention, can now be distilled to essentially recover both the 1-butanol as distillate bp. 117.7 C and DMF as pot residue bp. 152-154 C. The 1-butanol can be used in subsequent batches (it does not need to pass specifications since it does not encounter product). The DMF would need to be further purified to meet specifications if it is to be reused.

Note that in this example I chose 1-butanol to be the 'secondary solvent' to mix with my DMF because I expect there would be good hydrogen bond association between the alcohol hydroxyl and the amide while the two have a large difference in boiling points for the subsequent separation. If I were trying to separate a mixture of water and DMSO, I would choose toluene as my secondary solvent because I know there is good association between sulfolane which also has the sulfone functionality and all aromatics.