Switching Solvent at Scale: Using a Minimal Stirrable Volume Chaser

Working at laboratory scale one can switch from a reaction solvent to a work-up/extracting/crystallizing solvent by evaporating the reacting solvent to dryness on the rotary evaporator adding the second solvent and scrapping and stirring the oily neat solid off the walls of the flask and back into solution. So long as consideration is given to not decompose the solutes there is no problem.

With a few kilograms, using a large rotovap containing polypropylene beads to trap solids, the same thing can be done. The free-flowing beads trap the solutes; then, they can be redissolved in the second solvent and the polypropylene beads filtered.

In the pilot plant removing polymeric beads from the reactor is not possible. Evaporation to dryness is not possible. A possible solution might be to add into the reactor an inert, high boiling fluid in a volume such that the total volume of the non-volatile solutes plus this fluid reached the minimum stirrable volume. Now the first solvent could be distilled out of the reactor completely because at the end there would remain the minimum stirrable amount of non-volatiles containing all the non-volatile reaction pot contents.

What should be the properties of a minimum stirrable volume chaser? Well if we are going to get it separated from the reactor components of interest by extraction it must be immiscible with some standard organic solvents. This suggests that if the reaction products of interest are at least moderately polar the volume chaser should be a high-boiling paraffin. Such a chaser would be immiscible with either methanol or acetonitrile. Polar or semi-polar compounds would easily be extracted out of the paraffin phase. The paraffin chaser could be saved, drummed off, and reused for repeats of the same reaction.

Traces of paraffin can be removed from methanol by forming the insoluble complex with urea. The complex and excess free urea would be filtered off from the methanol solution.

In the event that the desired reaction products are more nearly apolar, the volume chaser should be itself polar. Liquid polypropylene glycol or glycerol can be used. These will work because the desired reaction components as an oil in either of these can be separated by liquid-liquid extraction with any organic solvent that isn’t appreciably miscible with them. Traces of either polypropylene glycol or glycerol can be precipitated as complexes with anhydrous calcium chloride at an appropriate point in the work-up.

A final possibility is to use a chaser fluid that can be removed in some other way. A possibility of this type would be to use acetic anhydride bp. 140 C which would drive over many solvents that are not reactive with it and that can be subsequently hydrolyzed to acetic acid which can be removed in water followed by an aq. bicarbonate extraction.

In a similar way, quinoline could be used as a chaser then washed out as a salt in water and recovered by subsequent basification of the aqueous extract.     

Thiazolidinedione as a Potential Reagent for eliminating Carbonyl Impurities from a Reaction Mixture: Purification by Reaction and Extraction

The development of the glitazones (pioglitazone, rosiglitazone etc.) as  drug substances has reduced the price of 2,4-thiazolidine-2,4-dione which is used in these syntheses. 

R=H

KiloMentor has always been attracted to the idea that some neutral carbonyl impurities could be quickly separated away from a complex reaction mixture using chemical agents that would react with the crude and give rise to products that could be extracted into another liquid phase.

Several such methods have already been popularized. For example, that aldehydes and ketones could be separated from materials without these functional groups by treatment of a mixture with semicarbazide adsorbed on silica gel was taught by Suk Dev. These derivatives could be subsequently hydrolyzed and recovered from a cyclohexane solution (so long as they were soluble in this solvent). Another KiloMentor blog promoted formation of oximes which offered two possibilities for solid separation: as a crystalline derivative itself or a hydrochloride salt of the oxime. Oximes have been cleanly decomposed to recover the ketone using many different reagents.

Thiazolidine-2,4-dione, it would seem, is a reagent that could be used to separate a carbonyl component, present as an impurity in a reaction mixture, where a non-carbonyl substance predominates and is the constituent of interest. This works because the condensation product between thiazolidinedione and a carbonyl along with any excess thiazolidinedione reactant will dissolve in a strong base because the thiazolidinedione has an acidic salt-forming imide functionality. It must be noted though, that the carbonyl compound itself cannot be regenerated. This is different from what was possible in the cases already alluded to.

 Thiazolidine-2,4-dione has melting point of 123-126 C. It can be purchased for less than $100/kg. The reaction can be done in a melt of this compound with sodium acetate as catalyst. Thiazolidine-2,4-dione is known to react easily with both aldehydes and ketones to give condensation products at its reactive methylene. With ketones, a mixture of two geometric isomers may be formed but both products upon treatment with aqueous alkali can be deprotonated to salts that have the potential to be extracted into an aqueous solution. Thus, these products show promise to be separable from neutral non-carbonyl materials by liquid-liquid extraction. Although only aryl aldehydes and aryl ketones seem to have been used in the literature, there is no good reason why aliphatic ketones would not also react cleanly particularly in the presence of an excess of the thiazolidinedione reagent. Aliphatic aldehydes might be too sensitive and could polymerize.

US 4703052

In a typical such reaction, the aldehyde or ketone starting material (IV) and thiazolidinedione (VI) are combined in approximately equimolar amounts with a molar excess, preferably a 2-4 fold molar excess, of anhydrous sodium acetate, and the mixture is heated at a temperature high enough to affect melting, at which temperature the reaction is substantially complete in from about 5 to 60 minutes. The desired olefin of formula (III) is then isolated, for example, by mixing with water and filtration, to obtain the crude product, which is purified, if desired, e.g. by crystallization or by standard chromatographic methods.

A mixture of carbonyls or a single carbonyl impurity in a non-carbonyl product might be separated by treating the mixture with thiazolidine-2,4-dione and sodium acetate and acetic anhydride with or without a solvent in order to condense the more reactive compound with the thiazolidine-2,4-dione. This condensed product will have an acidic hydrogen on the imide which can be converted to a sodium or potassium salt that can allow extraction into an aqueous solution. The residual, more hindered carbonyl or the non-carbonyl containing compound will remain unreacted and can be recovered by treatment with an organic solvent in which it readily dissolves. Any excess thiazolidine-2,4-dione present will also dissolve in the aqueous alkaline solution.

This methodology would need to be demonstrated with a mixture of ketones with different degrees of steric hindrance. A similar methodology has been used by partially forming enamines with the more reactive of two carbonyls and distilling the unreactive compound away from the enamine substance. The method proposed here does not require that the compounds be sufficiently low molecular weight to be volatile.

CA2423978

The invention also provides a process for preparing the potassium salt or a solvate thereof, characterized in that 5-[4-[2-(N-methylW(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a salt thereof,  preferably dispersed or dissolved in a suitable solvent, is reacted with a source of potassium ion and thereafter, if required, a solvate of the resulting potassium salt is recovered.  A suitable reaction solvent is an alkanol, for example, propan-2-ol, or a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane, or water; or a mixture thereof.  Conveniently, the source of potassium ion is potassium hydroxide. The potassium hydroxide is preferably added as a solid or in solution, for example in water or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents. An alternative source of potassium ion is a potassium alkoxide salt for example potassium tertiary butoxide.  

EXAMPLES

Example 1 

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione, potassium salt

A solution of potassium hydroxide (0.56 g) in water (5 ml) was added to a stirred solution of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethyl]thiazolidine-2,4-dione (3.0 g) in tetrahydrofuran (30 ml) at 50°C. The solution was cooled with stirring to 21°C over approximately 1 hour, before the solvent was evaporated under reduced pressure to afford 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (2.90 g) as a crystalline solid.

Example 2

 5-[4-[2-(N-Methyl-N-(2-pyridy1)amino)ethoxyl benzyl] thiazolidine-2,4- dione, potassium salt

A stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]  thiazolidine-2,4-dione (3.0 g) in acetone (30 ml) was heated to reflux before a solution of potassium hydroxide (0.56 g) in water (5 ml) was added. After 5 minutes a clear solution was formed and the temperature of the stirred solution was lowered to 21°C over approximately 1 hour. The solvent was evaporated under reduced pressure to give the 5-  [4-[2-(N-methyl-N-(2-pyridyl)mino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (3.25 g) as a crystalline solid.

Example 3 

5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyI]thiazolidine-2,4- dione, potassium salt

A solution of potassium hydroxide (0.56 g) in water (1 ml) was added to a stirred suspension of 5-[4-[2-(N-methy1-N-(2-pyridy1)amino)ethoxy]benzy1]thiaz01idine-2,4- dione (3.0 g) in propan-2-ol (30 ml) at reflux. Within 5 minutes the solution became clear before a precipitate began to form. The stirred mixture was cooled to 21°C over approximately 90 minutes. The solid precipitate was collected by filtration, washed with propan-2-01 (1 0 ml) and dried under vacuum for 16 hours to afford 5-[4-[2-(N-methyl-N- (2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (3.14 g) as a white crystalline solid.

Found (%): C: 54.44, H: 4.53, N: 10.45; Expect: C: 54.52, H: 4.83, N: 10.60.

The potassium ion level was determined as 9.9% by wt (expect: 9.9%) by ion

chromatography. Water content (Karl-Fisher): 0.2 % by wt.

Example 4

 5-[4-[2-(N-Methyl-N-(2-pyridy1)amino)ethoxyl benzyl] thiazolidine-2,4- dione, potassium salt

Potassium t-butoxide (1.41 g) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (3.0 g) in ethyl acetate (30 ml) at reflux. The stirred mixture was maintained at reflux for 15 minutes and then cooled to 21ºC over approximately 1 hour. The solid was collected by filtration, washed with ethyl acetate (10 ml) and dried under vacuum at 50°C for 72 hours to yield the 5-[4-[2-(Nniet1iy1- N-(2-pyridy1)amino)ethoxy]benzy1]thiazo1idine-2,4-dione7 potassium salt (3 30 g)  as a white crystalline solid. 

 Example 5 

5-[4-[2-(N-MethyI-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione, potassium salt

A solution of potassium hydroxide (4.71 g) in water (5.0 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzy1]thiazolidin-2,4- dione (25.0 g) in propan-2-ol1 (250 ml) at reflux. The stirred mixture was maintained at reflux for 15 minutes and then cooled to 21ºC over approximately 1 hour. The solid was collected by filtration, washed with propan-2-01 (50 ml) and dried under vacuum at 60°C for 16 hours to afford the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]  thiazolidine-2,4-dione, potassium salt (26.6 g) as a white crystalline solid.

Pertinent reference

J. Org. Chem., 1956, 21 (11), pp 1269–1271

A possible common use

Friedel-Craft acylations usually proceed with o,p-orientation to an electron-donating aromatic substituent. It seems possible that the para-substituted product could preferentially react with an insufficient quantity of 2,4-thiazolidinedione  at its less sterically hindered carbonyl or if the reaction is reversible the para-substituted compound could produce the more thermodynamically stable product compared to the ortho-substituted compound and thus produce mixtures of predominantly unreacted ortho compound and thiazolidinedione adducts of the para compound. Upon dilution with water, the thiazolidinedione product may crystallize leaving unreacted ortho ketone or upon aqueous alkali/organic solvent partition the thiazolidinedione adduct would go to the aqueous phase and the ortho-substituted product to the organic layer.

Selecting a Reaction Solvent

Some statements in the chemical literature suggest that process chemists should be able to optimize most reactions to greater than 90% yield.  Whether this is true or false depends of course upon the meaning of the terms ‘most reactions’, ‘yield’ and ‘optimize’. 

Most reactions

For the statement to be true, I think its authors must be thinking of name reactions, reactions discussed for example in the series, Organic Reactions, or reactions taught in basic organic textbooks. That is, standard reactions that are taught with the expectations that their analogs can be depended upon to work in prophetic chemical schemes.  To go to the other extreme, the kind of chemical reactions that we encounter as mechanistic puzzles on grad school cumulative exams or reactions proposed to explain an unusual by-product; these, by their very designation as puzzles make the point that they operate because of special circumstances and are unlikely to be successful when applied more generally. 

Yield:

Going still further in restricting the claim, I think the term ‘yield’ in this aphorism also needs some refining.  The Kilomentor Blog, with its emphasis on organic synthesis chemical process development takes pains to distinguish between assay yield (assay value for product as a % of theoretical in the reaction mixture just before isolation begins), isolation yield (the weight of product meeting the specification as a percentage of the theoretical weight one could have obtained with a perfect isolation); and overall percentage yield, which is the weight of product versus the theoretic weight of product as a percent.  Perhaps assay yield is what the rule of thumb refers to.  Isolations from reaction mixtures tend to average about 80% and for the overall reaction yield to be 90% the product of assay fraction multiplied by the isolation fraction must be greater than 0.9. That turns out to require something like an assay yield of 94.8% and an isolation yield of about 94.8%.

Optimization:

Although the word optimize means to find the best combination of all conditions, when seeking an optimum is contemplated, every simple protocol requires that all the parameters being optimized be continuous ones (like temperature, pressure, time, molar ratio etc.) and not discontinuous ones ( like reagent or solvent choice). Thus statistical optimization is really not optimization that properly explores all the potential modes. In any case, optimizing is a theoretical action that assumes an infinite amount of time to perform experiments. As we know or can imagine, chemists and chemical engineers working in the real world have deadlines and the diminishing returns of our optimization efforts soon fall below the opportunity cost for our work on the next problem.

Experienced commentators say the most important discontinuous, discrete variable the manipulation of which can improve a  reaction [ besides the exact substrate for the reaction (which can only be peripherally modified for example by protecting groups without making the substrate irrelevant to the process being contemplated) and the reagent for the reaction (which is constrained to a known few)] is the solvent, for which there are many choices.  

 Important Parameters for the Solvent

Substrate Solubility:

Even though complete solubility of all the reaction ingredients is not necessary to obtain complete reaction and increased concentration, even to the point of using a heterogeneous mixture, is good for throughput; homogeneous reactions have fewer problems on scale up.  Mass transfer is more dependable with a single solution phase and homogeneous reactions are less dependent on thorough mechanical mixing. Because heterogeneous reactions require more mixing power and because mixing power does not scale up proportionally with volume, accepting a heterogeneous reaction makes it more likely that the scale up will be more complex.  

Nevertheless, the actual solubility of reactants may not be apparent to chemists upon mixing solids and the proposed volume of solvent.  A considerable time may be required to reach the equilibrium solubility because dissolution may be kinetically controlled.  Heating the solid component to reflux in the solvent and cooling may result in a solution or at least a finely divided suspension that quickly dissolves when the reaction is started.  Once a small amount of reaction occurs, the first traces of product may rapidly dissolve the remaining starting material even without what would seem to be the full requirement for solvent.  Also, the solubility of a solid reactant in the solvent alone may not be representative of the solubility in the reaction mixture.  

A mixture of solvents can provide a much higher solubility than a single solvent.  Even if the use of a mixed solvent means that the solvent cannot be recovered and recycled, the increased throughput from using a solvent mixture that increases the reactor capacity can be beneficial for the overall cost.  There is too much emphasis upon using a single solvent in organic process chemistry.  Solvent is actually rarely recycled.  It is too costly for a fine chemical plant and there are too many problems associated with meeting the COA for the recycled solvent.

Heat of Vaporization:

The heat of vaporization quantifies how adequately a solvent ‘buffers’ reaction exothermicity? A useful question to ask is, “For the exothermicity of the planned reaction how many times would the heat produced by a hypothetical instantaneous reaction vaporize all the solvent of the reaction?”  This compares the enthalpy of the reaction with the heat of vaporization of the solvent and the dilution together.  It suggests how efficiently the condenser would have to work, at the solvent's boiling point, if the reaction occurred, in the worst possible case, instantaneously.

Heat Capacity:

The heat capacity of a solvent controls how rapidly the temperature of the solution could rise when a particular reaction takes place and releases the energy of reaction. 

Ease of a Solvent Change:

How easy will it be to make a solvent change in order to use a different solvent for the isolation or to prepare for a subsequent reaction when there is no product isolation? Lower boiling solvents are easier to switch away from because they can be displaced by higher boiling solvents.  Kilomentor has suggested in other articles other options for switching solvents.

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 distils a portion of solvent as the azeotrope.

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 the desired reaction over other 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.

A Change of Solvent in a Process Step will more often than not dramatically change the Optimal Values of all the Other Variables

There is actually very little information about reactions that have been really thoroughly explored.  An exception is the Willgerodt reaction. The optimal reaction conditions for acetophenone have been investigated using statistical methods in thirteen different solvents  varying 4 parameters. [ R. Carlson, Acta Chem. Scand. 40, 694 (1986)].  The optimal conditions are dramatically different depending upon the solvent used in the reaction.

in the case of the Willgerodt reaction, the optimal moles of sulfur per mole of acetophenone varied between 2 and 17. The optimal moles of morpholine reagent per mole of acetophenone varied between 6 and 13.7. The optimal reaction temperature varied between 70 and 145 C and the optimal reaction time varied between 2 and 22 hours. In two of the solvents major side products were observed. In one solvent no product was obtained and in another a different substance was the major product.

In contrast, when the substrates were differently substituted acetophenones, PROVIDED THAT THE SOLVENT WAS KEPT CONSTANT, there was little variation from the optimum of the major parameters:

• the yields were in the range 88-95%
• the sulfur/acetophenone molar ratio at optimum varied from 7-10
• the morpholine/acetophenone ratio varied from 8.4-10.6 and 
• the optimal temperature varied between 116-133 C

Although the breadth of evidence is narrow since few reactions have been sufficiently broadly investigated, this points to a hypothesis that solvent is the most significant parameter in reaction optimization.  Because it is a discrete and not a continuous parameter, it is necessary to decide before optimization is started what solvent or pair of solvents (one could optimize with a binary mixture of varying proportions) to systematically test using your optimization algorithm.  

When a first candidate solvent has been identified, either by finding a literature example in that solvent or by trial experiments, then other candidate solvents can be found by comparing principle properties and choosing other solvent candidates by their proximity in principle property space to the solvent that is the original candidate. 

Actually it is impossible to make a general statement based on data about reactions optimized in different solvents because such data is so rare.

In order to optimize a reaction the most important thing to know is whether the reaction has ever been performed in a solvent that will dissolve the substrate you need to use as starting material. For example, if you have a polypeptide as starting material and the reaction you are planning has only been conducted up to now in heptane, this is not promising. Your peptide is most likely insoluble in heptane and when you use an alternative solvent all the optimization parameters will be different. Put another way, preferentially you want to start optimizing a reaction by running the reaction on your substrate in the solvent that was used in a successful literature example.  In order to start an optimization, one must be able to detect and quantify the desired product in a first reaction mixture.

A surprising corollary is that the most important information to have in advance of an optimization study is the range of solvents that have been used in the prior art for the proposed reaction.

Investigational vs Empirical Approach to Optimizing Reactions

One might have a thorough and correct theoretical basis for understanding what favours or disfavours a particular chemical reaction or, conversely, one might know nothing at all about the reaction.  Normally the state of knowledge is somewhere in the middle. Sometimes applying the generalizations offered by the literature quickly results in step improvements; sometimes this common knowledge fails entirely and leads away from the better conditions. 

Screening of Suitable Solvents in Organic Synthesis. Strategies for Solvent Selection

Rolf Carlson, Torbjorn Lundstedt and Christer Albano. Acta Chim. Scandanavica B 39(1985) 79-91. 

Using a Component of a Reaction Solvent Mixture to Control Exothermicity

A problem that presents itself on-scale, but which is not any difficulty in the laboratory is the exothermicity of many chemical reactions.  It is much easier to control the temperature of an exothermic reaction to a narrow range of reaction temperatures than to do so in the plant. The reason, of course, is the much lower ratio of total volume to surface area in the laboratory.

Upon scale-up, exothermic reactions that do not suffer from this difficulty are those in which the reaction temperature is the reflux temperature of the reaction solvent.

An idea that might be useful in scaling down reactions so that they become more transferable to the plant would be to use a binary solvent mixture for exothermic reactions comprising in major part that solvent which is selected on the basis of the facilitation it provides for the particular reaction mechanism, for example, a dipolar-aprotic solvent for an SN2 nucleophilic substitution such as DMSO, and a minor solvent component that is chosen to have a boiling point at the desired reaction temperature. The minor solvent, of course, must be inert to the reaction conditions and must not at a level that inhibits the required reaction. For example, acetone might be combined with DMSO to maintain an upper reaction temperature of 56∞C. Acetone would not likely interfere with the substitution since it is also a dipolar aprotic solvent.

If a laboratory process was developed with such a mixture of solvents, there would not be any difficulty controlling the temperature of the reaction on scale up.  At the end of the reaction, if the isolation can more easily be conducted upon a mixture in 100% DMSO, the acetone can be distilled away. 

Another possibility for the minor component of the solvent mixture could be a solvent that forms an azeotrope with water so that the solvent combination could be dried in situ.

Another strategy for choosing a solvent for a reaction is to select the solvent from which the intermediate in the step is going to be finally crystallized. Although the substrate and reagents may not be substantially soluble in this solvent, this may not matter. The reaction may proceed even though a homogeneous solution is not immediately achieved. Indeed, based upon the work done with ‘on water’ reactions, almost complete insolubility can be a significant advantage. The advantage of homogeneous solution is most important for the ease of doing an in-process check for reaction completion rather than difficulties in getting a satisfactory reaction rate. The situation does not have the difficulty of a reaction without solvent at all where the absence of a material that can boil prevents the reactor contents from disposing of thermal energy and can lead to a runaway exotherm.

The phenomenon of reactions ‘on water’ often works because the water importance is not as a solvent for the reaction but it acts as a heat sink to modulate the exothermicity and increase the ‘minimum stirrable volume’.

In another situation, the substantial ‘on water’ phase is a buffer to remove an acid or base co-product that is formed but could interfere with further reaction. In brominations ‘on water’ the aqueous phase removes the HBr co-product.

Another solvent idea is dependent upon the fact that a 1:1 v/v mixture of DMF and cyclohexane is thermomorphic. At 60 C it is a homogeneous single phase but at 25 C it forms two separable phases. Chinese Chemical Letters Vol. 16, No. 8, pp 1017-1020, 2005 http://www.imm.ac.cn/journal/ccl.html

Important Secondary Considerations About Reaction Solvents

Besides the substrate and the reagents involved in a reaction, the factor that has the greatest influence on the outcome is the solvent. The solvent is the only species typically intimately involved in the transition state other than the molecules that contribute bonds that are either formed or broken. I would say it is the only molecules except for catalysts. Changing the solvent is almost guaranteed to change the enthalpy and entropy of activation. As a consequence a reaction optimized in one solvent needs to be reoptimized when transferred to another. The changes are quite likely to be substantial even when the solvent change seems to be slight.

Effect on Process Step Throughput

It therefore follows that solvent choice is first based on net contributions to the maximizing yield and reducing the occurrence of impurities in the crude. If there is still room for choice among equally acceptable alternatives its contribution towards process throughput is often the next most significant consideration. Intuitively one might think that the most important consideration is the solubility of the pure product in the liquid reaction medium. In fact on more thoughtful consideration, it is probably the degree to which the reactor liquid can dissolve the starting material that is most important for processing.  Think of it this way. It probably is not too important whether the product solidifies and falls out of the reaction mixture as the reaction proceeds. Indeed, one can think of equilibrium reactions that are only driven to good yields because the product or coproduct precipitates. The Finkelstein conversion of alkyl chlorides into iodides is driven by the insolubility of sodium chloride in the solvent acetone.  In order to achieve the highest throughput and the highest initial reaction rate it is probably important to get as high a concentration of starting materials into solution as possible at the beginning of the reaction. If the product as it forms precipitates from solution that is just another opportunity for simplifying the isolation.

It is easy to mistake the rate of dissolution of a substrate or reagent for its equilibrium solubility and select a higher solvent dilution for a reaction than is actually necessary. A second mistake that is possible is to think what is important is the solubility of starting materials at ambient temperature rather than at the temperature at which the reaction is going to be conducted. Solubility of most materials increases markedly with increases in temperature. Finally, the mixture of substrates and reagents gives a mixture and mixtures of solutes typically dissolve more readily than a pure single solute. Furthermore, as the reaction gets started the presence of product and co-products in the mixture will likely increase the dissolving power of solvent yet again.  The net result is that you would be surprised how little solvent is actually needed to produce a homogeneous reaction mixture for at least that portion of a reaction’s course required to give a good outcome.  Particularly for the early reaction steps of a process getting high mass throughput can dramatically reduce costs by reducing the number of batches.

Reaction solvent selection in batch process chemistry campaigns does not need to be confined to single solvents; mixtures of solvents can be used. An argument often heard is that pure single solvents should be employed in order to facilitate recycling and reuse of solvent to reduce the overall cost. This seems simple and straightforward except that solvent recycling in fine chemical processing is surprisingly rare. One of the reasons for this is that using recycled solvents requires that the user validate the process for using recycled solvent and set and consistently meet some certificate of analysis requirements for the solvent stock. Yes, it is true that many generic API suppliers recycle solvents and even reuse some solvents without purification (ie for recrystallization) but these appear to be exceptions rather than the rule.

Theories of solvation recognize that certain portions of a substrate are better solvated by one solvent and other portions by a second solvent; as a consequence the overall solubility of a substrate can be enhanced in a judiciously selected mixture of these solvents.  The widespread use of load cells to weigh solvents into a reactor has eliminated the problem of getting a consistent mixture of solvents at the beginning of reaction. On the other hand, a real downside of solvent mixtures is that the solvent composition in the reactor during the transformation varies somewhat depending upon the holdup of the reflux condenser and this holdup varies depending upon the particular equipment setup.

A reaction may proceed well even if there is no point during the processing when the reactor contents are homogeneous. This would seem to present a further opportunity to increase throughput by putting more substrate and reagents into each reactor load. The difficulty, that should not be overlooked, is that in-process checking for reaction completeness is typically made more difficult if the reactor contents are heterogeneous. If a starting material is not completely soluble how can one assay for it in the reactor? If the desired product is partially undissolved how does one assay the product in the reactor? A good assay is not possible. It is possible to perform quantitation upon both phases from a sample and this can tell something about reaction completeness but it cannot give a good assay and besides the procedure is more complex and less robust.

It is possible that no additional liquid medium at all may be needed for a reaction step. In some cases a liquid anti-solvent is sufficient to allow the reaction to proceed. In the case of reactions where substrate and reagents are insoluble in water, reaction ‘on water’ may be beneficial. The water drives the reactants together and serves as a medium for mass and heat transfer in the reaction vessel.

As the concentration in the reactor increases the rate is expected to increase. This may cause too exothermic a reaction or the reaction time may be so short that there is insufficient time to perform the in-process analysis to determine the best end point for the reaction period. Either of these can set a limit on the minimization of solvent and the throughput one can aim for.

Effect on Reaction Telescoping

Usually only when the yield and purity are acceptable from all the candidate solvents does one have the luxury of selecting from a group of possible solvents. In this fortunate circumstance one solvent may be preferable because it facilitates telescoping of reactions which can eliminate isolations that do nothing more than lose good material.

Solvent Additives to Improve Properties

Sometimes a second solvent is added to a first in small amount to change the physical properties of the liquid medium in some more desirable way rather than to change the bulk properties of the liquid. The addition of toluene in small amounts to DMSO for example is done to prevent it from freezing at such a high temperature when cooled. Something similar could be applied to cyclohexane, glacial acetic acid, or t-butyl alcohol solvent systems.  The addition of a small amount of a lower boil solvent can assist in maintaining a predetermined maximum reaction temperature and to increase the apparent heat capacity. 

What can Limit Throughput at Scale?

When conducting organic synthesis on a large scale in a kilolab, pilot plant or plant, a key factor that effects cost is the throughput of the equipment; that is, how much product can be produced how rapidly. Since most new organic chemicals are produced in employer’s semi-continuous batch reactors whose sizes are fixed, more production cannot be achieved just by using more or bigger reactor units and their peripherals. More material must be squeezed out of each run and/or the speed of iterations increased. Consequently, it is wise to think at the very outset about what factors in each process step limit its increase. What factors can limit the throughput of a reaction step with fixed plant equipment?

1. Risk of a Catastrophic Loss

Sometimes there is a scale of reaction that involves such a large commitment of expensive materials that your organization would not be ready to risk everything in a single reaction. This arises most frequently when the process is just being developed. At least with two or more small runs, they argue, we will deliver some product. It is less likely that everything will be completely lost. This situation most often arises towards the end of a long unbranched sequence of reaction steps.

2. Exothermicity of Concentrated Solutions or Large Volumes

For larger volumes or concentrated reaction mixtures, cooling becomes increasingly difficult as scale increases. How much can be loaded in a reactor may be limited by the cooling or heating capacity of the reactor.

3. Viscosity/Stirrability of Concentrated Solutions

The concentration of the reactants in homogeneous solution can sometimes be increased by reducing the amount of solvent, but this must stop when the mixture becomes impossible to adequately stir even if this thickening is only a transient event in the procedure. I once had a reaction that worked well except that at scale during the quench the mixture became so thick that it set and stopped the agitator. In the lab, the speed of the quench addition was so rapid we never saw the thickening.

4. The Ability to Sample Dependably for an IPC

It is possible that a reaction could be concentrated by reducing solvent without affecting yield or purity even beyond the point where it becomes heterogeneous, but the question must be asked, "Will sampling using the technology available to me at scale (for example by sucking up a sample through a dip tube), be able to accurately identify the correct stopping point for the reaction? Getting a representative sample for analysis from a heterogeneous reaction mixture is difficult. It may be even more difficult, even for practical purposes impossible, using the different sampling equipment available at scale. Incidentally, a reaction in the plant should not be so fast that product is destroyed by over-reaction before the result of an IPC for reaction completion is returned to the plant from the analysts.

5. The Size of the Equipment Needed for the Workup, Isolation and Purification

It is not just the maximum stirrable volume in the reactor that limits how big one can go. It is the ancillary equipment. An obvious exemplary case here is when steam distillation is needed in the work-up. The volume of water mixed with volatiles that needs to be collected in steam distillation is routinely much, much, larger than the reactor volume. If you are going to do it you need to have planned how you will handle the volume of water mixed with product that distils.

6. Storage Stability of an Isolated Intermediate

Using semi-continuous reactors, product made by a sequence of chemical steps is normally produced ‘campaign style’. This means that the first step is done batch after batch in the reactor and the first intermediate accumulated, analyzed, and stored temporarily. Then the second reaction step is performed over and over until the first intermediate is completely processed; and so on and so on until the desired final product is complete. This campaign style method has the advantage that the reactors and peripheral equipment do not need to be as thoroughly cleaned between uses as they would need to be if a different reaction were being performed next. (This is because the trace chemicals that could be left in the reactor and reactor train from any one of the reaction repeats are always the same).There are also advantages relating to the familiarity gained by the operators with repetition.

You would not be able to accumulate as much material before you use it, if an intermediate has limited storage stability and that might limit the extent to which that intermediate can be accumulated and hence the scale at which you can operate.

7. Addition time required (for reagents or quench or work-up)

If, when you double the scale or double the concentration, the overall run time of a batch also doubles,  you have not increased your throughput, since you could have done two batches at half the scale in the same time. This increase in duration of a batch as the scale increases is most likely to occur when there is a long addition, a long filtration or a long drying in the process step. In effect the process time is no longer proportional to the reaction time. Some other unit operation is limiting.

8. Maximum Stirrable Volume

This is the usual limiting factor in the laboratory. It is determined by how much volume is needed in the reactor at the point in the procedure when the volume is at its highest. For large scale reactions without other complicating factors this limitation also holds.

9. Scrubbing Capacity

If your reaction involves evolving gaseous materials that cannot be let out into the atmosphere, the off gases must be scrubbed. With a large throughput of material a large quantity of gases can be produced quickly. The reactor’s ancillary scrubbing system must be insufficient to treat them.

10. Foaming Tendency

You may think that the volume of your reactor is sufficient to contain a particular scale but what if there is vigorous foaming at some point? You need to make allowance for this foaming or make process changes to control it before you reach scale.

11. Production Scaled to Sensitive Reagent Packages

Some reactions, such as LiAlH4 reductions, use sealed prepackaged reagent sold in a particular molar amount. The package is placed into the reactor and when the appropriate solvent is added the package dissolves in the solvent freeing the reagent for reaction. The prepackaging avoids handling of dangerous materials by workers, avoids degradation of the reagent during measurement and does not leave partial packages of unstable reagent to be stored for later use. The method does limit the throughput to what can be obtained using an integral number of packages of reagent.

12. Rate of Gas Addition

For reactions that have a constituent that is gaseous, the reaction rate may be controlled by mass transfer of that gas into the liquid phase where reaction occurs. High throughput procedures  because the reactor is usually more completely filled characteristically have less gas-liquid interface. This is because the liquid in the reactor is not as deep when the reactor is only partially filled yet the surface area of the liquid even without stirring is the same. Stirring less liquid can be done more vigorously introducing more bubbles than can be done in a filled reactor.

13. Rate of Solid Addition

At scale, most preferably, solids are added in total, then the reactor is closed, inerted, then solvent is added and then liquid or gaseous components. Sometimes, however, the addition of a solid must be done later in the process. Solid can be pumped in as a slurry in a solvent or dissolved in a solvent and added as a liquid solution. Thus, the solid addition suffers from the restrictions on adding liquids; that is, because of restrictions of the piping, the addition may be of longer duration when the concentrations and scales increase because mass transfer is not as simple.  

Breaking Emulsions: an Urgent Matter during Scale-up

As one scales up a chemical process development step, one of the potential problems that I have found difficult to foresee is emulsion formation.  In about 4 years of experience the single most frequent cause for a call in the night from the pilot plant production management is an unpredicted emulsion, which interferes with a separation of two liquid phases. When one of these emergencies occurs, it is a blessing to have whatever you know about solving the problem assembled in a single place, because quite a few people are waiting for your instructions.

Emulsions are caused, it is said, by the repulsion of same charged particles which are residing in the droplets of one of the liquid phases. According to this principle the emulsion should be destabilized by ions of the opposite charge. Higher charge increases the efficiency of discharging the offending ions. Thus K⁺< Ca²⁺< Al³⁺ and similarly Cl^- <SO₄^2-.  According to this thinking aluminum sulfate should be a great agent to dissolve in water for breaking an emulsion.  This is theory, mind you, I have never used more than ordinary salt.  The addition of sodium chloride to break an emulsion would not be the first thing to try because it is irreversible; that is, once the salt has been added it cannot be taken out again if you change your mind.

Raising the temperature of the mixture of liquid phases very often leads to breakup of the emulsified layer and a clear separation of phases.  The rationale is that the separation of phases is a kinetic difficult; the phases are inherently essentially immiscible all that is needed is to speed up the rate.  Whether you can do this must take into account the stability of the desired product but this is rarely a problem for the amount of warming that is probably needed.  The advantage of the warming answer is that it is reversible.  If it fails just go to plan B.

If one examines closely a portion of the emulsion, one can sometimes get a useful clue to the course of action that will work.  Sometimes the more vigorous stirring in the plant setting has suspended small gas bubbles in the droplets of one phase causing them to float rather than settle. These gas droplets can also be associated with some sediment that is suspended therein as well.  Application of vacuum to a gently stirred mixture of the partially emulsified reactor contents can cause these bubbles to break resulting in complete separation of the phases. This attempt is particularly easy to try in the lab on a 500 ml sample of emulsion from the plant. Just place the filled flask on the rotovap; rotate gently and apply a water aspirator vacuum.  Gentle warming is also easy to try out in this configuration. A note of caution should be registered here. You may see a clearing of the emulsion and there is a temptation to take the clarified two-phase mixture and for added safety filter it under vacuum through a pad of Celite.  This filtration can undo all the good you have done.  Sucking the last of the solvent through the Celite can put gas right back into the phases! 

Another possibility- notice all these ideas can be tried one after the other on the same sample because nothing has been added and it is not changed! Stirring the emulsion composition with Celite and then filtering can often break solid stabilized emulsions.  When the small particles of solid, which often carry those pesky charges are removed, the phases may separate easily. One should be on guard during this that an emulsion caused by the gas bubbles sucked off the Celite does not replace the solid stabilized emulsion.  Pressure filtration appears to solve this completely, which is fine since in the pilot plant the transfer is by pressure not vacuum.

Finally, an emulsion may be caused by a small amount of a surface-active ingredient.  Treatment with a material like activated charcoal that itself has a large surface area may be effective if the surfactant is taken out on the solid when it is filtered.

Addition of small amounts of an alcohol have also been known to help but remember these additions are irreversible and may affect other aspects of your planned isolation.

Finally if all these fail, you can perturb the system by adding a small amount of a concentrated solution of a salt but it should be the last resort because it involves the biggest irreversible change.