Diisopropyl Ether (DIPE) Solvent Can be Safely Used in Industry

 

Diisopropyl ether also trivially called isopropyl ether (analogous with ethyl ether) is an important anti-knock additive for gasoline. It is an important coproduct in the preparation of isopropanol by the hydration of propylene. As a result, it is reasonably priced.

In the Research Laboratory

In the laboratory setting, diisopropyl ether must be treated with great caution because, more than almost any prospective solvent, it readily forms explosive peroxides when exposed to atmospheric oxygen. Bottles of old solvent that are left in a laboratory or storeroom slowly evaporate through inadequately seals and the peroxides concentrate. Sometimes the peroxides even crystallize. Such residues or concentrates are extremely dangerous. If one of these concentrates is discovered, it must be handled by trained personnel with special safety equipment.

The consequence is this useful solvent does not get incorporated into scaled-up processes. This is unfortunate because at scale the dangers of the solvent are drastically mitigated. 

The Difference In the Plant At-Scale

In the plant, all process operations are executed under an inert atmosphere. This is part of standard operating procedures (SOPs). Vessels are closed. Transfers are made by piping liquids, solutions, or slurries. There is no pouring through the air! The possibility of exposure to oxygen in the air is remote. 

In addition, in the laboratory the formation of peroxides in diisopropyl ether is made more likely because exposure to light is increased and light can catalyze peroxide formation. In the plant light is blocked by working in drums, closed metal reactors, piping, and pumps. Reactions and processing involving DIPE occur either in subdued lighting or in the dark. There is no photocatalysis possible.

Finally, at scale, batch sheets require that all chemical inputs be tested to be sure they meet their specifications and one of the requirements for DIPE use is that it passes its requirement with regard to peroxide impurities. So unlike the situation in a laboratory where an old bottle of solvent might be used in an experiment, all the inputs for working in the kilo lab or pilot plant are rigorously tested. Furthermore, the capacity for the analytical testing laboratory to do retesting for peroxides during processing is also available.

So as we can show, unlike other materials, the higher danger point using diisopropyl ether occurs in the research laboratory during process research and development. Yes- special precautions need to be implemented -in the laboratory!

These laboratory dangers can be stymied a number of ways:

• Store in the dark 
• Keep bottle sealed
• Stabilize with butylated hydroxytoluene (BHT) or NaOH  
• Remove peroxides by acidic iron(II) sulfate wash
• Pass through alumina (does not destroy the peroxides; merely traps them)
• A more drastic method that also removes water/oxygen is to distill from sodium/benzophenone

But Why Bother Taking Any Risk?

DIPE readily separates from water-free sulfolane.

 

DIPE won’t separate from totally anhydrous DMF, but adding  a little water gives two layers.

 

DIPE does give phase separation from anhydrous DMSO. So you can do a reaction in dry DMSO and repeatedly extract the product into DIPE. 

A biphasic/phase transfer catalyzed reaction can be conducted using the DIPE/DMSO system. 

Diisopropyl ether (DIPE) is a clear liquid that is immiscible with water. It smells like decomposing green tea. MP: -60 °C; BP: 69 °C; Density: 0.725 g/mL . It has a reputation as a go-to solvent for recrystallizations that have failed with other solvents.

In addition to what has been established for sure, DIPE is promising in other ways. Reactions performed in dipolar aprotic solvents such as N-methylpyrollidone, dimethylformamide, N-methylformamide, dimethylacetamide and dimethylsulfoxide are often drowned out with water and then extracted to isolate organic products.  No cheap and convenient method has been worked out to separate these polar organics from the bulk of the water and return the dipolar aprotic to an anhydrous condition suitable for reuse.

On the basis of the physical properties of the chemicals, the following might be workable but KiloMentor has seen no experiment to substantiate it. 

Diisopropyl ether (DIPE) forms an azeotrope with water that is reported to boil at 62.2 C. This is a heteroazeotrope.  The designation means that this azeotrope’s vapor is in equilibrium with two immiscible liquid phases. According to the Chemical Rubber Handbook, DIPE and water form an azeotrope that on condensation splits into a water-poor DIPE-rich upper phase and a water-rich lower phase. Thus, addition of DIPE to a mixture of one of these higher boiling solvents and water, and boiling of the ternary mixture under a Dean-Stark trap with continuous return of the top DIPE phase could be expected to gradually separate a lower water-rich phase which could be periodically drained away. The high boiling solvent that is being dried would theoretically be retained throughout in the still pot.

In the real laboratory situation, however, a small amount of the high boiling solvent as vapor entrained in the reflux stream that one is trying to free from water could be all that is needed to prevent the distillate from separating into two phases in the trap and this would scupper the procedure so this concept would need to be tested. Nevertheless, if it works and your facility has unused distillation capacity, solvent recovery could be profitably practiced.

 It is crucial for a practical process that the DIPE be recycled since the distillate is 97% DIPE and only 3% water. Recycling is essential to be able to remove a large amount of water using only a small amount of DIPE. 

Before recovering the DIPE by distillation in the plant it should be tested for peroxides and washed with aq. acidic iron (II) sulfate if the peroxide test is positive.

Other solvents that boil above 100 C that can potentially be separated from water and dried using DIPE are nitromethane, acetic acid, dioxane, ethylenediamine, sulfolane, and isoamyl alcohol.

After the water has been completely removed continued distillation will drive over the DIPE itself. Even if small amounts of DIPE remained in a recovered dipolar aprotic solvent it is usually unreactive. Of particular importance… it is inert towards organometallic reagents.

A Trick for Using Acetone as a Crystallizing Solvent.

Acetone is a good solvent for many organic compounds. It would be advantageous if for crystallizations it could be diluted with a less volatile anti-solvent and then warmed at a low temperature to remove predominantly acetone to decrease the substrate’s overall solubility in the residual fluid so that it could be crystallized in good yield.

If this anti-solvent is higher boiling, however, the substrate is increasingly likely to oil out as the pot temperature rises. Preferably, therefore, the anti-solvent should form a lower boiling azeotrope with the acetone so that the acetone can be completely substituted at a temperature below acetone’s own boiling point of 56.2 ℃.

Fortunately, there are quite a few potential anti-solvents that form such azeotropes.

Low Boiling Binary Azeotropes of Acetone with Other Low-

Boiling, Organic Solvents

Azeotropes           v/v ratio b.p. ℃

Acetone/ 1-chloropropane    15/85         45.8

Acetone/ cyclohexane            67/33         53.0

Acetone/ cyclopentane            36/64 41.0

Acetone/ hexane           59/41          49.8

Acetone/ isobutyl chloride        73/27         55.8

Acetone/ diisopropyl ether        56.5/43.5 53.3

Acetone/ methanol          88/12         55.7

Note that the first five in the list lead to a less-polar mixture as acetone is removed. Diisopropyl ether leads to something of similar polarity while removing the azeotrope with methanol eventually gives a more polar medium as the acetone is driven off.

Using diisopropyl ether is to be discouraged since it can have such strict safety requirements.

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.

The 1,2-Diol Functionality as a Possible Phase Separating Tag

In CA2677670, a monoglyceride ester is separated from other impurities by absorbing the mixture on silica gel and washing with hexanes/ethyl acetate 90:10 v/v. This was not a column chromatography as can be determined from the experimental details. The 90:10 mixture of hexanes/ethyl acetate (10 ml) was used to dissolve the approx. 16 g of ester and to this solution 40 g of silica gel was added.  The slurry was put on a fritted funnel and eluted with 150 ml of the mixed solvents to remove the impurities. A second elution with 300 ml of ethyl acetate  removed the monoglyceride which was concentrated in vacuo. This seems to show that diols seem to bind tenaciously to polar solid adsorbants.

It is well known that mono alcohols often form insoluble complexes with CaCl₂, LiCl, LiBr, CaBr₂ and MnCl₂ for example. So it not surprising that diols would form strong complexes with such inorganic salts.  As evidence of this there is a patent, US 3,846,450 titled Purification of Oxygenated Compounds that describes the removal of diols by passing a liquid comprising some of these through solid alkali earth halides. This would trivialize their separation from compounds without this substructure. 

It has been reported that complex steroidal and prostaglandin structures can be purified by precipitating as LiBr complexes [GB2094795]. The prostaglandin structures typically contain more than one alcohol functionality. This should increase the likelihood that metal halide complexes with 1,2-diols are more likely to produce solid precipitates.  Kilomentor has already published a note about using such metal complexes to separate alcohols from non-alcohols and some alcohol mixtures from each other.

I have not found work showing that substances containing two or more non-adjacent alcohol groups dependably form lithium bromide or calcium bromide precipitates even though the work with lithium bromide and prostaglandin intermediates is promising in this respect. What is clear is that neutral 1,2-diols can be separated from other functionalities ruggedly and dependably.The 1,2-diol functionality most probably can be covalently attached to a very wide variety of intermediates as a ‘phase-separating tag’.

 Substrates containing the tag would, perchance, be precipitated by stirring with an inorganic salt in non-polar solvent. It might turn out that the 1,2-diol at the end of a hydrocarbon chain might be a substructure that could control precipitation in a wide variety of intermediates using a standard set of conditions ( a particular salt, precipitating solvent, ethanol catalyst and reaction conditions). It is already known for example that a primary alcohol is preferred to a secondary or tertiary one.

After the terminal 1,2-diol had served its purpose for intermediate isolation/ purification it could be selectively cleaved to an aldehyde or cleaved and reduced to a primary alcohol with one  fewer carbons than the diol. The functional group would be expected to work as a phase-separating tag best when the other functional groups in the intermediate were not polar ones that could also interact strongly with the inorganic salt.

It seems that whether a solid complex is formed may depend upon both the crystal lattice energy of the complex and the energy of the crystal lattice of the salt itself. As Sharpless notes, [K.B. Sharpless, A.O. Chong, and J.A. Scott, Rapid Separation of Organic Mixtures by Formation of Metal Complexes, J. Org. Chem., 40, 1252 (1975)}, whether they form solid complexes or not the alcohols do cause the dissolution of the calcium chloride into the hexane. Another important observation provided by Sharpless et al. was that mixtures of alcohols often dissolved but did not even partially precipitate under the complex forming conditions even when the pure components of the mixture formed solid calcium chloride complexes when treated individually but separately. 

Why some alcohols form solid complexes and others just dissolve the inorganic salt ,but do not precipitate, has been hanging unsolved for a long time. The Sharpless strategy has never become popular. This is because, according to a personal communication from Sharpless himself, the best conditions for forming and precipitating the complexes were unfortunately not those recommended in his article. Not a 2:1 molar alcohol inorganic salt ratio, but a large excess of inorganic salt works best taking into account more cases. Perhaps the alcohols and inorganic salt form oil-in-water or water in-oil emulsions which only occasionally break down to precipitated solid. 

If the problem is emulsion formation it might be important to remove completely any residual water. Using aprotic solvents that have fewer degrees of freedom themselves might help. Cyclohexane and diisopropyl ether might be tried. Diisopropyl ether seems to be the solvent of choice when it is difficult to get regular crystallization. Patent GB1555968 suggests that methyl isobutyl ketone (MIBK)or methyl n-amylketone are preferred candidates to form insoluble complexes, at least when calcium bromide is used.

Clearly solvents must be used that do not themselves dissolve these divalent inorganic salts because such solvents present in so large an excess would easily out compete substrates.  Hexanes, methylene chloride, MIBK and methyl n-amyl ketones would meet the criterion of not dissolving much salt alone.

Besides the equilibrium effect sometimes giving rise to useful precipitation there is probably also a kinetic effect upon whether the precipitation/crystallization provides purification. The limited data could be interpreted as suggesting that small alcohols exchange more rapidly than large alcohols and small alcohols, present catalytically, promote exchanges. 

Triethylamine as Reaction Solvent and Workup Extractant

Triethylamine is more often thought of as a reactant or acid trap. It is inexpensive enough, however, to be considered for a role as a reaction solvent.

 Triethylamine has a critical solution temperature with water. Below 18°C they are miscible but immiscible above this temperature. Thus it is thermomorphic and this provides a potential for simplified isolations.

Triethylamine is likely to dissolve neutral or basic substrates which can deliver hydrogen bonds without actually causing proton transfer.  Alcohols, phenols, amides, N-hydroxyl amides, thioamides, primary and secondary amines, meet the criterion. 

As a solvent it could not be used in oxidizing environments because of the ease of forming an N-oxide or the loss of one of its lone pair electrons.

A reducing environment would not cause any problems. Its' use would be problematic in the presence of electrophiles since it would tend to compete to react with them. Halides, epoxides, etc. are incompatible. With acidic substrates it would be inclined to form salts. It should be compatible with organometallic agents and indeed may stabilize these.

Triethylamine has a boiling point of 90°C. It does not form explosive peroxides like diethyl or diisopropyl ethers. It can be expected to be close to diethylether in solution properties. It might be useful as an extraction solvent so long as the substrate being isolated is not electrophilic. In the same way that liquid ammonia can be a reaction solvent so could triethylamine.

Uncommon Solvent Immiscibilities

 KiloMentor is always on the lookout for methods to separate components of a mixture by partitioning between immiscible liquids. Better known ones are methanol or acetonitrile with hydrocarbons. Many different solvent pairs may show immiscibility between ambient temperature and -20 C and this temperature range is easily accessible inside a jacketed reactor where liquid-liquid partitioning is done at scale. It is in the laboratory that this temperature range is inconvenient to achieve.

Below are listed some less-common immiscible pairs that may prove useful.

Dimethylsulfoxide - Xylene

Dimethylsulfoxide - Diethyl Ether

Dimethylformamide - Xylene

Dimethylformamide -Diisopropylether

Trichloroethylene - Xylene

Acetic acid - Hexane

Methyl t-Butyl Ether (TBME) -Sulfolane

The DMF /Diisopropyl ether immiscibility suggests that one look for an Upper Critical SolutionTemperature (UCST) between DMF and TBME at below room temperature. A small amount of water could be added to the DMF to raise the UCST.

Since DMSO and diethyl ether have immiscibility it suggests that one explore for a UCST between DMSO and TBME below ambient temperature.

What would the miscibility be between a mixture of xylene and diethyl ether with DMSO? Both xylene and diethyl ether are separately immiscible with DMSO.

To get rid of the diethyl ether suppose we try a mixture of xylene and TBME with DMSO?

How about a mixture of DMSO and trichloroethylene with xylene? Both DMSO and trichloroethylene are separately immiscible with xylene.

Dimethylsulfoxide or DMF reactions could be worked up by extraction into m-Xylene followed by azeotropically removing the xylene as an azeotrope with water after cold extracting the xylene to remove residual dipolar aprotic solvent.

Both m-xylene and isopropylbenzene form azeotropes with water that can be used to quickly remove the organic as a clean phase. Can either of these be useful for isolating organics formed in the solvents DMF or DMSO? You tell me- I’m retired; you have a lab.

Reaction Solvents that could be Worked-Up with Acetic Anhydride

Solvents that could be distilled away from acetic anhydride (bp. 140 C) and taken up into any solvent immiscible with acetic acid, after the hydrolysis of the acetic anhydride chaser and admixture with a little additional water to enhance immiscibility of the two layers:

Chlorobenzene

Nitro propane

Methyl chloroacetate

Cyclopentanone

Diethyl carbonate

Dimethyl sulphite

Tetrachloroethylene

2-nitropropane

Methylisobutyl ketone

N-methylmorphiline

Nitromethane

Toluene

1,1,2-trichloroethane

Trifluorotoluene

1,4-dioxane

Nitromethane

Methylcyclohexane

Heptane 

Propionitrile

Dibromomethane

Dimethylcarbonate 

Trichloroethylene

Isopropyl acetate

1,2-dimethoxyethane

Fluorobenzene

1,2-diethoxyethane

1,2-dichloroethane

Cyclohexane

Acetonitrile

Cyclohexane

Benzene

methylethylketone 

2-methyltetrahydrofuran

Ethyl acetate 

Butyl chloride

Carbon tetrachloride

Petroleum ether

Hexane

Diisopropyl ether

Chloroform

Perfluorohexane

1,1-dichloroethane

Methyl acetate

Carbon disulphide

Dimethoxymethane

Pentane 

Diethyl ether

Methyl t-butyl ether

The Potential Use of Acetic Anhydride/Acetic Acid for Enabling Solvent Switches during Work-Ups

Each reaction in a chemical process has solvents in which the conversions works better and the preferred solvents for consecutive reactions in a scheme are usually different. As a consequence, performing solvent switches is essential for telescoping process steps thereby avoiding unnecessary intermediate isolations.

The boiling points of acetic acid and acetic anhydride are respectively 117 and 140 C. Both acetic acid and acetic anhydride are quite inexpensive and they are biologically trouble-free.

Acetic acid is infinitely miscible with water and is an excellent solvent for broad classes of substrates. Mixed solutes dissolved in acetic acid lead upon water addition to decreasing solubility of most organic compounds.

Acetic anhydride is a solvent that reacts with solute molecules that have nucleophilic functionalities and particularly those with what is termed 'active hydrogens'. Because of its even higher boiling point, acetic anhydride can chase many lower boiling solvents during distillation. It can then be, itself, converted by hydrolysis to acetic acid, optionally neutralized with aqueous alkali, and washed away from lipophilic materials. Heating a solvent mixture in which acetic anhydride is a constituent dries it. Only enough acetic anhydride needs to be added to a crude product to provide liquidity, then distillation instituted until all the first reaction solvent has been removed. Even if an acetate ester or amide is formed during isolation, that can be reversed by alkaline hydrolysis after the solvent of the first reaction is removed.

Because acetic anhydride has a bp of 140 C, it can chase many different first solvents. Just considering those that boil above 60 C they include diisopropyl ether, pet. ether, carbon tetrachloride, butyl chloride, methyl ethyl ketone, benzene, cyclohexane, chlorobenzene, acetonitrile, methyl chloroacetate, 2-nitropropane, MIBK, nitroethane, toluene, 1,1,2-trichloroethane, trifluorotoluene, 1,4-dioxane, nitromethane,  methylcyclohexane, heptane, propionitrile, cyclohexene, 1,2-dichloroethane,  fluorobenzene, 1,2-dimethoxyethane, 1,1-diethoxymethane, trichloroethylene, tetrachloroethylene, dimethylcarbonate, and diethylcarbonate.

 

Consider for example acetic anhydride’s potential for changing from the high boiling solvent chlorobenzene to ethyl acetate. In such a scenario, a mixture of chlorobenzene and acetic anhydride could be distilled to remove chlorobenzene and some acetic anhydride. The still-pot residue would comprise acetic anhydride and non-volatile reaction mixture components. This residue does not solidify because of the presence of the acetic anhydride. The minimum stirrable volume is maintained. Water is added along with the new second solvent which must be water-immiscible, in this case, ethyl acetate. Dilute mineral acid or base may be added to accelerate hydrolysis of the acetic anhydride. The acetic acid or acetate anion dissolves in the aqueous phase and is cut away. The reaction mixture is left dissolved in ethyl acetate.

In a different scenario, if the first solvents are low enough boiling, acetic acid itself can serve as the chase liquid for distilling away the first solvent. The product may not be particularly soluble anhydrous acetic acid or the acetic acid can be subsequently diluted with water used as an anti-solvent to cause precipitation or the acetic acid can be optionally neutralized and washed away with water after adding the new water-immiscible second solvent.

Acetic acid itself forms azeotropes with many common solvents that reduce the temperature at which they can be removed: butyl ether, chlorobenzene, cyclohexane, cyclohexane, tetrachloroethylene, trichloroethylene, toluene and xylene are among these.

Unjustified Shortcomings of DMSO as Reaction Solvent

 

 It is true that DMSO has no known azeotropes. This and its high boiling point account for the difficulty of removing it from reaction mixtures. 

It is not true that DMSO is difficult to dry. DMSO distilled under vacuum after taking a forerun is water-free. 

Whatever its disadvantages DMSO is too valuable a solvent to rule it out.

DMSO is reported to be immiscible with cyclohexane, heptane, hexane, pentane, 2,2,4-trimethylpentane, and diethyl ether, so these liquids can be used in solvent/solvent extractions. Silylation of the solutes in a reaction mixture should improve their extraction into these less polar solvents which can provide a second layer with DMSO.

DMSO is reported to be miscible with methyl t-butyl ether (MTBE). Based on the reported immiscibility with diethyl ether, this would not necessarily be expected. Perhaps adding a small amount of hydrocarbon to the MTBE could provide a two-phase mixture. An anhydrous DMSO produces a phase separation with diisopropyl ether (DIPE) according to the “Solvent of the Week” website. This would permit more flexible liquid/liquid extractions to separate a product from DMSO.

Another potential way to work up reactions done in DMSO could be to concentrate the solution as much as possible under vacuum, and then add the minimum stirrable volume of glycerol (enough to still provide some slight agitation even if the DMSO gets completely removed) and displace the remaining DMSO, still operating under vacuum. Then,  any suitable solvent that is immiscible with glycerol (there are many) could be added and the substrates of interest taken into it. Mixtures of solvents both immiscible with glycerol can be used to increase the extraction’s effectiveness.

Paraffin can also be used instead of glycerol as the chaser for DMSO and this could be useful if the substrate you are trying to recover is polar. Then, extraction from paraffin into lower alcohols becomes possible since these alcohols will be immiscible with the saturated hydrocarbon (paraffin) medium.

A Quicker, More Thorough Method for Choosing a Solvent for Your Reaction

 

In Acta Chemica Scandinavia B 39 (1985) 79-91, lead author Rolf Carlson has made some suggestions for choosing a solvent for a reaction. He feels an important consideration will be to be sure that a sufficiently wide range of properties is explored. At the same time, he recognizes that solvents that have already been used successfully in the literature for similar or analogous reactions or those selected in the literature for reactions that seem likely to follow similar mechanisms will be attractive. Our experience also suggests that solvents that won’t dissolve the reactants usually fail. In most cases the liquid medium needs to be a single fluid. 

His proposal produces a two-dimensional map using Eigenvector projections of the solvent descriptor space. I do not adequately know what that means and I don’t suppose it matters whether you do either. What matters is that if you choose one solvent from the central regions of each quadrant, such as chlorobenzene, diisopropyl ether, nitromethane and N-methyl-2-pyrollidone, there will be less probability that you will miss out on being directed towards an especially advantageous but less-obvious solvent choice. If it is obvious that a particular solvent picked from one or more of the quadrants will be unsuitable, choosing another from the same region can still maintain a diversity of solvent properties.

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?