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.

Continuous Chemical Flow Reactors that Scale Well are not New

Even back in 2013 when this blog was first written, continuous flow reactors were increasingly popular. They have been available commercially for many years. They have become mechanically sophisticated in their pumping and controls. But even in Organic Synthesis Coll. Vol. III pg. 172 the synthesis of Carboxymethoxyamine Hydrochloride is described and it uses a continuous flow reactor in the first step.

The reactor works by gravity flow and is made from simple glassware and operates at 100 C using steam heating.

The procedure can be expected to work for reactions that are slow at room temperature or below but procedure rapidly at 100 C. The Organic Synthesis procedure combines acetone oxime with bromoacetic acid using an aqueous base:

“A mixture of 612 g. (4.4 moles) of bromoacetic acid and 500 g. of crushed ice is chilled in an ice-salt bath and made distinctly alkaline to litmus with sodium hydroxide ( about 440 g. of a 40% solution). During the neutralization, an additional 500 g. of ice is added. To the solution are then added 292 g. (4.0 moles) of acetoxime and 440 g. of 40% sodium hydroxide (4.4 moles), the temperature being held below 20 C during the addition of the alkali. The mixture is then allowed to flow dropwise, during 3-4 hours, through the inner tube of a steam-heated Liebig condenser (jacket 75 cm. long; inner tube 10-mm diameter; angle of inclination about 20 degrees) into a 5-l. round-bottomed flask cooled with running water (Note 2).”

Note 2 says that “[b]y this procedure, the reaction takes place in a few seconds, and the formation of by-products is minimized. If the solution of the reactants is heated in bulk, the reaction temperature cannot be controlled and a lower yield is obtained of a dark product which, however, can be purified by distillation under reduced pressure.”

The total throughput can be calculated to be 2784 g of solution which passes, in we can approximate, about 3.5 hours. That is 13.3 g. per minute. The actual duration that material is heated within the steam-heated 100 C zone is determined by the angle of declination of the condenser tube. One can imagine that using instead of a Liebig condenser an Allihn condenser,  that has a series of bulbs through which the liquid must pass, would imitate the effect of a series of continuously stirred tank reactors and the condenser would not need to be so long to have the heat contact time.

Practical Recyclable Chiral Acid Resolving Agents for Making Diastereomeric Salts: Lasalocid and (-)-DAG

When performing a chiral resolution at-scale it is important whether the resolving agent can be re-isolated, crystallized to a consistent purity, and thus practically reused. When the resolving agent is a carboxylic acid, this is simpler when the carboxylate salt of an alkali or alkaline earth metal is soluble in water while the free acid precipitates from water. Two common chiral acids have this characteristic: lasalocid and (-)DAG.

Lasalocid

Lasalocid sodium is a veterinary pharmaceutical available in large quantities. It is a chiral carboxylic acid that can be used to form diastereomeric salts with racemic amines. Based on tested examples it is predicted to work most dependably for primary amines that have their chiral center at the alpha or beta position as well as tertiary amines with a proximate chiral center with respect to the nitrogen atom. The ligand is capable of multipoint binding with the amine as it forms hydrogen bonds to many different oxygens. The ligand contains many different chiral centers. The molecule is made by fermentation. The acid is relatively inexpensive. It was covered by US 4,129,580 which expired in 1998.

(-)-2,3;4,6-di-O-isopropylidene-2-keto-L-gulonic acid hydrate also called (-)-DAG

(-)-DAG is also a water-insoluble chiral organic acid that can be used to resolve chiral asymmetric amines.

It is a relatively inexpensive compound that is used an intermediate in the synthesis of Vitamin C.  It was first prepared by Reichstein et al. Helv. 17, 311 (1934). Its use for resolution was taught in the expired US patent 3,682,925 (1972).

Reactor Cleaning: Where Organic Process Chemists Can Help Chemical Engineers in Process Development

For simplification in the operation of the plant, chemical engineers prefer a standard cleaning protocol no matter what process step has preceded it. This is often possible but for it to be workable without exception is wishful thinking. A standard protocol cannot take into account different substrates, different products, different processing conditions, different materials of construction, and the variety of different pieces of equipment in the reaction/isolation/purification train.

Because chemical engineers cannot as easily detect strongly adhering contamination in the larger equipment, they often learn about a problem far along in the development. The process chemists, in contrast, often working in transparent equipment that they clean themselves can be aware at an early stage when a cleaning difficulty is likely. Furthermore, so long as they know the standard cleaning protocol in the plant they are in a perfect position to know that it is likely to be seriously challenging.

Discovering an optimized reactor cleaning protocol can be regarded as unsophisticated stuff but it makes nonsense of our efforts to improve throughput with optimal processing conditions if, in fact, the reactor cleaning takes an order of magnitude more time to perform than the entire process! It very often can be easier and cheaper to improve throughput by reducing cleaning time by improving the cleaning protocol.

Reactor cleaning in API production is the most obvious situation where the process chemist can alert the engineers. It is in the reaction zone where highly insoluble, often polymeric, often baked or charred materials can become attached to the equipment. It is such impurities that provide the greatest challenge to cleaning methods because they cannot usually be treated by the physical abrasion of scrubbing. If an impurity can transfer either in solution or as a particulate downstream into the isolation/purification equipment that ability to migrate suggests an upper limit to the cleaning difficulty. Since it could be moved down the equipment chain it should be able to be moved out of the equipment entirely!

Neil G. Anderson in his monograph, Practical Process Research & Development, says nothing about reactor cleaning other than providing a reference to the article by I.I. Valvis, W.L. Champion Jr. “Cleaning and Decontamination of Potent Compounds in the Pharmaceutical Industry.”

Org. Process Res. Dev. 1999, 3, 44.  This latter article pertains to cleaning the residues from final products of known activity rather than unknown mixtures of compounds of unknown but probably low activity. Although the gunk that is tenaciously retained in the reactor zone is physically intractable it is likely not bioavailable.

The process chemist can do laboratory experiments in a fashion that will be more likely to show up such a gunking problem at an early stage. These difficult contaminants are often created when the reactor contents splash onto the vessel walls above the surface covered by solvent. This occurs in the plant because the entire wall of the reactor is heated not just up to the level of the reaction solvent. If in the laboratory the reaction flask is only lowered into the oil bath up to the solvent line, there will be no corresponding surface for this gunking to occur on and it might not be observed. To mimic more closely the process reactor both portions of the flask below and above the solvent line need to be heated.

When at the end of the reaction period the reaction vessel is visibly contaminated to an extent where hot reaction solvent will not make it visually clean, a scale-up problem is possible and potential solutions need to be considered in advance.

At the very least the process chemist should record and retain information about what was tried and what seemed useful in removing the visible impurities. It would also be useful to know at what point the impurities became apparent, whether they were deposited above the solvent level, below it, or in both places. Sometimes the gunk is more concentrated near the point of addition of some reagent or it may accumulate on the stirring paddle or the stirring shaft to a greater extent. 

The chemist may be able to make some useful guesses about the mechanism for producing the impurities and whether, for example, the impurities derive from a co-product (which will not be reduced in the optimization) or from a byproduct that could be reduced by optimizing. Since very often these dark-colored, low solubility substances are polymeric, consideration might be given to how a radical chain inhibitor might change things.

Polymers can also often be reduced by technologies that create an environment of high dilution for one or more of the reactants.

Definitions

Full cleaning is the more thorough cleaning protocol used when a different process step or a different product is going to be produced next in the reactor being cleaned. This is also referred to as decommissioning cleaning.

Partial cleaning is the less thorough cleaning protocol that is applied when the same process step is to be repeated next in the equipment. Some residual detectable contaminants are acceptable since they are the same as will be produced by the repetition of the step.

Boil outs, rinses, and swabs are three different methods for obtaining a sample to analyze to determine the extent of the cleaning.

A boil out is performed by refluxing a solvent in a closed reaction system in order to clean its interior surfaces and provide a sample of the residues in solution. The cleaning effectiveness of a boil out is a function of dissolution, mixing shear, and vapor extraction all resulting in an exponential dilution cleaning profile.

A rinse sample is performed using spraying or misting nozzles to send solvent where boil out would typically be impossible as for example in piping or portable equipment.

A swab sample is obtained by wiping a surface with solvent-moistened cotton gauze and it is used to grossly quantify the presence or absence of a contaminant.

Since boil outs result in exponential dilution profiles, equal results from two consecutive boil outs are sufficient to validate cleanliness.

The most common solvent to use in boil outs is methanol. Because it is miscible with water it does not form two phases even if the reactor is a bit wet. Although it is a good cleaning solvent for drugs since to be bioavailable they must have some solubility in water and hence likely some in polar organics, it is not necessarily good for process intermediates that may be very hydrophobic.

Acetamide is a solid at normal pressure mp 81℃ but it is liquid under reduced pressures: bp₇₆₀ 222℃; bp₁₀₀ 158℃; bp₄₀ 136℃; bp₂₀ 120℃ ; bp₁₀ 105℃ ; or bp₅ 92℃ . According to the Merck Index, 1 gram of acetamide dissolves in 0.4 ml of water, 2 ml of alcohol, or 6 ml of pyridine. It is also soluble in chloroform, glycerol, and hot benzene. Merck reports molten acetamide is reported to be an excellent solvent for many organic and inorganic compounds. It has been reported to be the most universal of all solvents. The high temperature required for melting and vaporizing the material will increase the dissolution. Under vacuum, the conditions for a boil-out are obtained in the reactor. Molten acetamide or condensing acetamide vapor can be expected to dissolve both organic and inorganic compounds.

Another idea for removing gunk would be to reflux the azeotropic mixture of diisobutylketone (isovalerone) and water. The minimum azeotrope boils at 97.0 C. When the azeotropic composition condenses it splits into two immiscible phases: 53.4% relative volume of >99% diisobutylketone and 46.6% of >99% water. Thus it is possible to boil out with a constant boiling mixture that applies a pure organic liquid of low surface tension to all the equipment surfaces.

Alternatively, using the azeotropic composition of the diisobutylketone reduction product, 2,6-dimethyl-4-heptanol and water (29.6% alcohol and 70.4% water) a constant boiling azeotrope can be boiled out in the system that upon condensation returns to immiscible alcohol and water phases. 

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 synthetic chemistry laboratory skills, quick access to questions pertinent to real laboratory skills and knowhow. 

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 can select questions at random so as 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 totally truthful. False claims are common; some verification of knowledge and experience is essential and that 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 knowhow 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 interviewer and candidate. Sometimes questions assess how a candidate reasons from what is provided.

Candidates are well advised to immediately admit to the interviewer that they should acknowledge questions 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, 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

With reference to fractional distillation, what is a 'pig'?

In words or a sketch, describe a kugelrohr assembly.

What is the meaning of 'star', with reference to 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' with respect to 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 a  '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, in order 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 colour or substantially reduce the colour'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? Alternately, 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 the 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 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 which 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 a 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 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 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 delivered a 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 elations 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 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 shifting’ 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?