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..