Interesting Solvent Possibilities: Ternary Thermomorphic Azeotropes that Break upon Cooling into Two Similar Volumes of Liquids

Warning: 

The author is unaware of any examples of reactions running in either of the proposed thermomorphic solvent systems. Neither is he aware of any work-ups, purifications, or product isolations performed using the two phases into which these azeotropic compositions separate on cooling. 

Testing these ideas would make an excellent undergraduate research project for a college student majoring in organic chemistry. Furthermore, the result if positive would be publishable!

Introduction

Using thermomorphic phases to try, by liquid-liquid extraction, to separate a mixture of very similar compounds may have advantages compared with trying the same technique using more typical pairs of poorly miscible liquids because the thermomorphic phases would likely be more similar to each other than two ordinary immiscible solvents and so offer a better chance to display significantly different partition ratios even for quite small differences between solute components.

Thermomorphic solvent systems provide two distinct liquid phases within a first temperature range and a single homogeneous liquid phase within a second different range. 

Using the upper and lower phases from a thermomorphic azeotropic composition, first as a reaction solvent and subsequently, as the two immiscible liquids of a counter-current extractive separation might be simple and convenient. It would seem that the ratio of volumes of the two phases needs to be conserved in all the liquid-liquid extractions that are attempted. Otherwise, the two phases will cease being immiscible. Also, the proportion of solvents to substrates must be kept relatively large so that the substrates do not disturb the proportions of solvents distributed between the two thermomorphic phases. 

 There is reason to believe that a complex organic substrate with both hydrophilic and hydrophobic segments will be more soluble in a mixed solvent made up of more and less hydrophilic constituents. This would suggest that a thermomorphic liquid would be a better reaction solvent for such a substrate than most pure solvents. Thus the thermomorphic mixture could be a good choice for the initial chemical reaction part of a process step.

In the work-up part, the reactor contents would be cooled down to the temperature range where two liquid phases appear; the layers would be physically moved into different vessels and each liquid reextracted with the correct volume of the other immiscible thermomorphic phase. The separation would proceed in exactly the same fashion as a standard counter-current extraction with the added proviso that the correct ratio of volumes of the two immiscible phases be maintained in every extraction

Finally, the composition in the separate portions from the counter-current process is analyzed and the pure fractions are combined and concentrated.

In the laboratory version of this technique, each separate phase can be vacuum evaporated to dryness and redissolved in hot thermomorphic single-phase and cooled down to separate.

 Two inexpensive thermomorphic solvent systems that separate into comparable volumes of two immiscible phases are provided below.

  Ethanol/Toluene/Water Ternary Azeotrope

One such composition is an azeotropic mixture of ethanol, toluene, and water boiling at 74.4 C, which has a composition of 37.0% ethanol, 51.0% toluene, and 12.0% water. 

The distillate from it separates into two immiscible liquids with the upper layer composition having a 15.6% ethanol, 81.3% toluene, and 3.1% water composition and a specific gravity of 0.849.  This upper phase constitutes 46.5% by volume of the distillate. 

The lower phase of specific gravity 0.855, consists of 53.5% of the total volume and is 54.8% ethanol, 24.5 % toluene, and 20.7% water. The low difference in specific gravities between the two immiscible phases suggests that the phase separation may be slow.

Whether this will be a difficulty will need to be investigated.

Ethanol/Heptane/Water Ternary Azeotrope

A mixture of ethanol, heptane, and water forms a ternary azeotrope boiling at 68.8 C which has a composition of 33.0% ethanol, 60.9% heptane, and 6.1% water. The distillate separates into two immiscible liquids with the upper layer composition being 5.0% ethanol, 94.8% heptane, and 0.2% water. The specific gravity of the upper phase is 0.686.  The upper phase constitutes 64.6% by volume of the distillate. The lower phase of density 0.801 constituting 35.4% of the total volume, is 75.9% ethanol, 9.1% heptane, and 15.0% water.

Another ternary thermomorphic combination is isopropanol/toluene/water.

Modes of Combining Reactants in Chemical Process Scale Up

Direct, Inverse, and Simultaneous Additions: Direct vs Indirect Addition

In this blog, I will speak about additions in reactions. Direct additions are defined here as additions in which at least the reagent is added to the substrate.

Inverse reactions are defined here as additions in which at least the substrate is added to the reagent.

Simultaneous Additions are defined here as additions in which at least both the substrate and the reagent are added, at least partially simultaneously, to the reactor.

Fast and Very Fast Reactions

The mode of addition in a process step becomes particularly important for fast or very fast reactions. A fast reaction will be defined here as one in which there is more than at least about 5% of the product or an intermediate that leads on to product present in the flask at the half-addition point.

A very fast reaction will be here defined as one in which there is only a trace of one of the substrate or reagent being added if the addition is stopped and the mixture analyzed after at least 5% of the addition has occurred.

These definitions are based on the half-addition test recommended by R. Carlson which teaches that to discover whether the rate, order, and direction of addition is going to affect the purity and/or yield take a sample for analysis at the point when half the addition has been completed. The choice of the rate and direction of addition in a process step can be particularly consequential for either fast or very fast reactions.

Is the Stoichiometry ever realized in the Reactor?

When we think of a chemical reaction, we normally think of the substrate and the reagent reacting together according to the stoichiometry of the balanced equation that we have written. That is:

x S (Substrate) + y R (Reagent) → z P (Product) + w C (Coproduct)

where the integers x, y, z and w are selected to balance the chemical equation.

In fact, except for reactions where the rate of reaction is slow compared to the rate of addition (direct or inverse) of substrate with reagent, this instantaneous stoichiometric ratio is never really approximated at any time in the reactor.

In the laboratory, where it is very easy to cool the reaction flask because it has a high surface to volume ratio, it may be possible to do an addition quickly, without worrying about a runaway exotherm, and to get concentrations close to the reaction equation’s stoichiometry in the reaction flask.

Also in the laboratory, one can combine reactants with solvent in the stoichiometric ratios at a low temperature in the reaction vessel and then warm them up to the reaction temperature. When this can be done it is possible because the cooling capability in the lab under favorable circumstances can be greater than the exothermicity: nevertheless, even in the lab for many reactions such as Grignard formation, this protocol more often results in an uncontrollable reaction.  In any case, certainly, these protocols cannot be considered for reactions on scale.  Generally when large quantities of chemicals are involved one reactant is added very gradually to a mixture of all the other reactants at a temperature sufficient to cause all of the added chemical to be essentially immediately consumed so that there is no build-up that can fuel an uncontrolled exotherm that might otherwise set in after the addition was complete.

When a solution of the reagent is being slowly added, it encounters the full equivalents of the other reactants, creating ratios of reagent to other reactants very far from the ratios expressed in the balanced equation.  The result is that any undesired reactions that have a higher molecularity in the reactants already completely in the flask and an equal molecularity in the reagent being added will have an increased tendency to occur and may produce an undesired by-product.  The main point here from the process chemist’s perspective is that this tendency will be exaggerated at the scale increases because as the scale increases it is mandatory to have longer addition time. 

For example, in the situation where reagent R is being slowly added to Substrate S aiming to get product P; if the substrate S can react with an intermediate I, and if the addition rate is slow compared to the rate of reaction; you are very likely to get the reaction:

I + S → I-S (where I-S is an overreaction product) because the intermediate I is being formed quickly at the beginning of the addition when it will be still in the presence of a very large excess of the unreacted substrate S. Thus by the law of mass action intermediate I will have an increased likelihood to react with all the S, which is concentrated in the reactor.

In a similar way, in the situation where reagent R is being slowly added to Substrate S aiming to get product P; if the product P is reactive with the starting material you are very likely to get some reaction:

 P + S → P-S (where P-S is an overreaction product) because at the middle of the reaction there is much more substrate S than reagent R to encounter the initially formed product P.

In each of these situations an inverse or simultaneous addition needs to be considered. There are corresponding situations where the direct or simultaneous additions are preferable on this theoretical basis.

Additions in the Laboratory

Additions in the laboratory can be very fast indeed. One can pour 100 ml of solution into a 250 ml r.b. flask in a few seconds.  On scale it is not possible to copy this. The absolute volume of solution is much more; it must be pumped in or run in by gravity through a constricted line; besides, the enthalpy change would most likely be unmanageable.  For these reasons, the rate of addition becomes a variable of significant concern in scale up because when we go to large reactors the addition rate is severely constrained compared to the lab situation.

Besides the instantaneous addition of a solution, which I have just posed as an example which is simply impossible other possibilities are seriously discouraged on scale.  In the laboratory so long as a strong stream of inert gas is maintained over the reactor surface and the reaction vessel is in a fume hood, a glass stopper can be removed briefly and a solid reactant poured in through a powder.  The equivalent would not be acceptable in the chemical plant. The operators would be exposed to chemical contamination, as would the atmosphere in the plant and the inertness of the reactor atmosphere would be seriously compromised.  Also, the addition would not be adequately reproducible and if there were solvent already in the reactor when the solid addition was made there could be a dangerous splash back.

A number of reactions require the slow and controlled addition of a solution containing one reagent to another. These are ideal for scale up. Slow addition is both necessary and simple to achieve on-scale; rather, the technical difficulty that the process development chemist needs to solve is how to duplicate in the laboratory these slow additions on scale to model the process.  

Techniques to Provide Slow Additions at Lab Scale

Attempting to control the flow rate over a number of hours using a conventional constant pressure addition funnel is a frustrating exercise.   An inexpensive way to increase the sensitivity of an addition funnel is to use a Teflon stopcock modified with a groove cut in it. This will allow one to open the stock-cock more gradually by slowly exposing the groove leading to the cylindrical channel in the plug to the liquid in the funnel rather than having to expose partially a circular hole. I first read about this idea in the Laboratory Manual, Research Techniques in Organic chemistry, Robert B. Bates and John P. Schaefer, Foundations of Modern Organic Chemistry Series Prentice Hall Inc., Englewood cliffs, N.J.1971. p. 14.

The Herschberg dropping funnel is the classical method for slow controlled additions in the laboratory. These have been further improved by making the pressure equalizing side arm to follow the Mariotte principle that assures the drop rate regardless of the liquid level. Internal delivery scale is graduated to allow accurate resetting on successive runs. Such a funnel is shown in a Figure in Fieser & Fieser Vol. 1 pg. 783 (under 1,4-pentadiene).  These funnels are now called constant-addition funnels and can be obtained from commercial glassware suppliers.

Syringe pumps are alternative means to provide consistent very slow additions on a laboratory scale that can mimic the rates of addition that may need to be used on-scale.

An (expensive) peristaltic pump or syringe pump overcomes these problems but can introduce other complications. An additional advantage however is that using dual syringe injection two different solutions can be simultaneously slowly metered by the same mechanism.  Such a use is described by E.J. Corey and Eric Block, New Synthetic Approaches to Symmetrical Sulfur-Bridged Carbonyls, J. Org. Chem. 31(6) 1665-6 1966.

With the use of a syringe pump, there are obvious difficulties associated with purging the solution and assembling such an apparatus under nitrogen, and Peter Osvath [. J. Chem. Educ. 1995 72 658] reported a simple and inexpensive homemade apparatus that can replace the single syringe pump rate of addition. A Male Luer Lock tip (recovered from a broken syringe) was sweated onto the flattened tip of a pressure-equalizing addition funnel and a syringe needle was attached. Judicious selection of needle length, bore size, and reactant volume can be used to control the addition time simply and reproducibly. With a 250-mL funnel, the flow rate changes by <25% from the beginning to the end of the addition. (In fact, a reduction in the rate of addition may even be advantageous as the reaction proceeds, the reagent in the receiving flask is consumed, its concentration drops, and the rate of reaction will decrease). A piece of fine Teflon tubing of appropriate length attached to the needle can be used to reduce the flow rate even further, but this is only necessary for very slow rates of addition. For example, the time of addition of 200 mL, of an ethanolic solution could be varied from approximately 5 minutes (150mm/17 gauge) to approximately 5 h (200mm/22 gauge), and once the addition time for a particular needle length/bore is determined, the tap on the addition funnel is turned fully on, so no adjustment is necessary. When needles with a particularly fine bore are used, a small plug of glass wool should be inserted in the constriction above the tap, to filter the solution and prevent blockage of the needle. An inert atmosphere is readily maintained throughout the system. 

For the slow addition of only about 5 ml another technique has been described [Goran Magnusson, J. Chem. Educ., (56) 410 1979] which is prepared from two disposable pipettes and a short length of latex tubing. A drop rate of as low as one drop every 20 seconds is easily obtained even with low-viscosity solvents such as ether.  

High dilution apparatus built with a dilution chamber can also be used. A classical example is the apparatus used in the Acyloin reaction for preparing large ring systems.

[N.J. Leonard and C.W. Schimelpfenig, Jr., J. Org. Chem., 23, 1708 (9158)].

In such high dilution apparatus there are two aspects: 

1. The actual rate of addition of the reagent or substrate that is controlled by the dropping funnel apparatus. This is most often a Herschberg dropping funnel and 

2. The dilution of the reagent/substrate upon entering the chemical reactor. This is controlled by the dilution chamber size and the rate of the refluxing of the solvent.  

The first factor controls the absolute concentration in the bulk of the reaction solution and the second controls the concentration of reactant in the unmixed addition stream at the point of entry into the reaction mixture. In a completely homogeneous reaction the first is almost exclusively important but for heterogeneous reactions occurring on the surface of catalysts or on solids insoluble in the reaction mixture the second is also of significance.  The acyloin condensation of esters to α-ketols is thought to occur at low concentration on the surface of the molten sodium metal.

The addition of liquid reagents with relatively high freezing points should often be diluted with solvent when they are being added into a cold reaction mixture to prevent the reagent from freezing in the addition tube.

Gaseous or low boiling reaction constituents can often be preferentially added below the surface of the reaction mixture because this ensures more complete absorption into the mixture; otherwise, the low boiling material may be lost in the off-gases perhaps accelerated by an appreciable local exothermicity at the point of addition.

In very fast reactions where the rate of reaction is competitive with the rate of mixing, it may be advantageous to spray the solution being added unto the surface of the reaction mixture thus providing smaller droplets, faster effective mixing, and a higher surface area to promote the reaction.

Reactions that are likely to be sensitive to the rate and mode of addition can often be predicted in advance on the basis of a general understanding of the mechanistic details. A susceptible reaction is characterized by the presence of an intermediate or the final product that once formed can react with another equivalent of starting material. The result is that at a point during the addition the intermediate or final product is present along with a substantial amount of starting material or starting reagent. If this situation persists for a considerable time as it often does when the addition period must be prolonged as in scale-up, the by-product production will rise.  This situation can be mimicked in the laboratory by stopping the addition at some intermediate point, stirring for a time commensurate with the expected total addition time on scale, and then completing the addition and proceeding with the process step. If the step is susceptible to this problem the amounts of impurities will rise.

Checklist for Developing a Scaled up Step in a Chemical Process

Do the reaction conditions dissolve or scratch the reactor?

The reactor and auxiliary equipment need to be protected.

Are any isolated intermediates likely to be genotoxic?

Such intermediates, if unavoidable, should be telescoped with the next step or held in solution.

If the process involves a crystallization step: 

• Is a method in place to determine the solvent composition?
• Is there a method in place to determine the ratio of volatile solvent to non-volatile residue?
• Is there provision to initiate crystal formation? (ie seeding)
• Is there a provision for managed crystal growth?
• Is there provision for crystal size assessment?
• Is there a study of crystal aging(ripening)? Does the purity change depending on aging?
• Is there an IPC to verify that the crystallization is complete and the correct quantity of residual product is left? 

Does the process have a filtration process step? If so: 

• Has the rate of filtration been checked?
• Does the solid shrink in diameter size on the filter after removing solvent or does the filter cake crack?
• Do your instructions make provision to prevent shrinking or cracking to facilitate washing?
• Have you done a split run (reaction mixture is worked up in several parts) to assess the effect of inadequate washing of the crystalline mass?
• If the filtration uses charcoal or filter-aid, has the substrate been completely removed from the filter material? Do you have an in-process control to assess the quantity in the filtrate and the quantity caught in and on the adsorbant? 

In the process is there a concentration step or a distillation? If so:

• Has the stability of the hot solution been determined on the time scale of the large reaction?

Does the process have extraction steps? If so: 

• Are the phases susceptible to emulsion formation (vigorous shaking)?
• What provisions for promoting separation are known?
• Are the phases very dark and hard to tell apart? What to do about this?
• What about interfacial material? What should be done with it?
• Have you reduced the size of the liquid phases as much as possible to increase throughput?

Is there a drying step in the process? If so: 

• Can the drying be done by azeotropic distillation or by passing it through a molecular sieve plug to avoid solid drying agents?
• Is there an IPC to determine completion of drying?
• Can you perform a final rinse with a more volatile anti-solvent to accelerate drying?

Process Chemistry Definitions used by Kilomentor

In the Kilomentor blogs particular terms are used. Their definitions are given here:

A chemical substrate is a reactant in a chemical transformation which contains a large share of the atoms which are intended to be retained in the target structure.

A chemical reagent is a reactant in a chemical transformation which is relatively inexpensive, usually commercially available, or available in just a few steps from cheap commercial materials and which contains a large proportion of atoms which are not intended to be retained in the target structure.

A by-product is a chemical substance which is formed during an attempted process step, which is not an intended or expected product.  Most frequently a by-product when it is produced consumes either substrate or reagents or both and is responsible for some loss from the theoretical yield.

A co-product is a product of a chemical transformation which according to the stoichiometry must be formed at the same time as the product and which is related in the rate at which it forms to the rate of formation of the product.

A catalyst is a material which changes the rate of a reaction but which is not consumed by the reaction.  True catalysts are needed in only amounts of 1-10 molar percent.

Assay yield is the calculated quantity of product material determined by analysis of the reaction mixture at the time when the reaction is deemed complete divided by the theoretical quantity of material that would be present after a quantitative conversion based on the limiting ingredient according to the assumed stoichiometry as a percentage.  The significance of the assay yield is that it is a measure of the completeness of the reaction process without any confounding interference from the effectiveness of the isolation of the pure product.

Recovery yield is the ratio of quantity of isolated product of adequate purity to take to the next step as a fraction of the calculated quantity of product material determined by analysis of the reaction mixture at the time when the reaction is deemed complete; such ratio  expressed as a percentage The significance of the recovery yield is that it is a pure measure of the efficiency of the isolation of the desired product from the reaction mixture.

Overall yield is the product of the assay yield represented as a fraction and the recovery yield represented as a fraction, converted to a percentage. This is the classical chemical yield that is described in the chemical literature.

Practical purity is the purity and the distribution of impurities, which is acceptable in an intermediate in order to obtain the required degree of purity in the target product.  The significance of practical purity is that it a pragmatic objective.  A low absolute purity of an intermediate is acceptable if the impurities are removed during the course of the subsequent steps or are removed in subsequent necessary purification operations.  Another goal of this measure is to highlight that it is wasted effort to introduce purification operations for an intermediate, when the impurities, which are being removed would be removed in subsequent manipulations.

A process step is defined as all the unit operations, which are combined in order to go from one point; where an intermediate can be accumulated, stored, and analyzed; to another such point in a batch process.  A process step differs from a reaction step.  A reaction step consists of all the operations required in practice to go from a set of  isolated starting materials and reagents to another isolated pure substance, which is on the reaction path.

Convergent synthesis describes a synthetic route in which large pieces of a chemical structure are assembled as individual targets and then these large pieces are couple together in the final operations of the synthesis.

  Convergent syntheses are mathematically more efficient than linear syntheses because the longest reaction path in a convergent synthesis is shorter than in a linear route. This is important, because the overall yield in a chemical synthesis is the product of the overall yields (each expressed as a decimal fraction).  The more linear steps, the more fractions that must be multiplied and the smaller the product will be.

A phase switch in a reaction or isolation is the mass transfer of a chemical intermediate, co-product, by-product or reagent from a first phase where it was resident during a reaction or isolation to a second phase.  Most frequently this is a transfer from one liquid medium to a second immiscible liquid medium as in an aqueous-organic extraction, but a phase switch could for example be a distillation in which the volatile materials are converted from liquid to gas or a crystallization or precipitation where a substance passes from a liquid solution into a solid.  The importance according to Curran who popularized the concept, is that the more phase switches the chemical intermediates pass through the more robust the separations in the process are, because at each phase switch there is the potential to leave impurities behind in the second phase

.

Some Phase Switches

Freeze drying

Adsorbtion of aromatic-like materials on charcoal

Solubility/insolubility in methanol (inorganic salts)

Silver nitrate complex formation in solution or adsorbed on silica gel

Steam distillation

Crystallization

Short path distillation-molecular distillation

Counter-current extraction

Solubility insolubility in ether, cyclohexane, carbon tetrachloride or toluene

Co-distillation with a high boiling hydrocarbon

Addition of saturated salt solution to a DMF solution-precipitating the product and salt

Dissociation extraction

Derivatizing agents which give precipitated or extractable solids

Derivatizing polymeric materials

Sodium bisulfite derivatives of aldehydes

Claisen alkali

Sulfur trioxide

Fuming sulphuric acid

Calcium chloride, calcium bromide, lithium bromide complexes

Enamines of ketones

Girard P or Hydrazinobenzenesulfonic acid

The Resolution of Racemic Alcohols through the Half-Acid Oxalate Esters.

A New Synthesis of Optically active Myo-Inositol 1- Phosphates, Tetrahedron Letters (50) 4791-4794, 1971 is as far as I can see the only paper teaching any use of acid oxalate esters.  This is surprising since the introduction is so simple, the addition to the molecular weight is small as derivatization goes, and the reverse of the reaction can be done by oxidation under neutral conditions to complement acid or basic hydrolyses that can lead to rearrangement for some substrates.  The use of the oxalyl chloride reagent has become routine in the laboratory since this paper was published for the preparation of acid chlorides. What is not touched upon in this paper but is the main attraction for the KiloMentor is the potential for these half-ester half acids to be extracted into an aqueous phase as their salts, thus achieving phase-switching purification of an alcohol.  Mention is made in the paper that upon recrystallization some of the oxalate group is lost with the regeneration of the starting alcohol but this should not be a problem if the derivative is only intended to provide a temporary handle for phase-switching of the salt. It seems from the example that these derivatives can be prepared from even quite hindered secondary alcohols and the alcohol recovered without loss of stereochemistry.

The procedure provided for making the half oxalate reports treatment of DL-1,2,4,5,6-penta-O-acetyl-myoinositol (I), which has one free hydroxyl, with a 5-fold excess of oxalyl chloride in pyridine-chloroform at -10 C and subsequent hydrolysis (dilution with water) to give the acid oxalate (II) in 83% yield, m.p. 191-193 C (with decomposition; from CHCl₃-ether)

The decarboxylation that restored the alcohol functionality without rearrangement of the acetate esters was done by oxidizing “with lead tetraacetate in the presence of cupric acetate in pyridine/dioxane under argon (30 C, 5 hr)…”

Oxidizing with lead tetraacetate on-scale is regarded as troublesome; however, a  non-aqueous work-up which  destroys any excess Pb(IV) by reducing it with oxalic acid (which is oxidized to carbon dioxide) and then adding further oxalic acid to precipitate lead (II) oxalate (water solubility 0.65 mg/ 100 ml of water) which is then filtered should work well. 

Other half esters that can serve the same phase-shifting purpose are phthalate, succinate, and maleate; however, these cannot be removed by oxidation.   

Avoiding the Screw-up from Left Field with a Full Process Vision

Some process chemists will find themselves as small cogs amongst large teams whose goal is to develop new specialty chemicals or pharmaceuticals.  As a scientist whose contribution is to apply highly specialized knowledge, you may be bunkered in a rather isolated trench or silo within your organization. Your mission may be defined for you rather narrowly so your undoing may come from an irrefragable requirement that comes from outside your silo and that is imposed so late in your work plan that it really means starting over.    

A powerful organizing structure for pharmaceutical product development is presented in an article by Pradir K. Basu, Ronald A Mack, and Jonathan M. Vinson, “Consider a New Approach to Pharmaceutical Process Development, “ Chem. Eng. Prog., 95(8), 82 (1999).  It seems intended to reduce the likelihood of the above misfortunes.  

Process chemists, as knowledge managers, need to press at an early stage in their work for some mechanism within the wider team so that these must-have ‘requests’ from outside your core group reach you before your work is too far advanced. 

Much of the referenced article presents no more than standard reminders of the importance of cost considerations throughout discovering a synthetic method, scaling it up, and putting it into production for a process to manufacture a new pharmaceutical. This is the pharmaceutical business with the marketing, selling and regulatory functions stripped away. Its importance to corporate profitability does not engender much debate. The importance of the article is that their concern is broader. 

The authors are concerned about the efficient execution of a plan that starts after identifying a candidate to be a commercial drug with a salutary effect on a biological target and proceeds to the validation of manufacture for that molecule at a commercial scale. 

The enhanced approach that they propose identifies what they call ‘process vision’ as the core organizing principle. The definition and exemplification of the expanded concept of ‘process vision’ is the article’s significant accomplishment. 

The authors help us understand different aspects of this 'process vision' at different points in the article. For me, I cannot say I adequately grasped what they were getting at until I drew particular phrases together from my notes. Some of these quotes, drawn from different parts of the essay are: 

 “The process vision satisfies all essential requirements, including those for safety, quality, waste minimization, cost, time, and operability”. 

“The process vision is neither the process with maximum yield nor the one that gives maximum product purity…..it is neither a chemist’s vision nor an engineer’s vision; it is not even the vision of the chemists and engineers together.” 

“It is a vision that all stakeholders in development, manufacturing, and marketing can share…..” 

Reading between the lines and amplifying certain aspects, the process vision emerged as a policy statement that provided, as a starting point, standards by which team members coming from each stage of the organization's endeavor (laboratory process, kilo lab, pilot plant, and manufacturing facility) could satisfy downstream colleagues’ concerns from the outset of their own work. The authors' specific examples of the unique orientation and emphasis that players at the different stages have and which they want to see addressed from the very outset reinforce my interpretation. 

This early overview, whose importance they emphasize, can be expected to show up inevitable cross purposes and improve the odds for early compromise and conflict resolution. 

They write:

 “Chemists think in terms of steps, reactions, yield, purity, and so on; engineers in terms of unit operations, physical properties, heat load, and the like; manufacturing personnel in terms of throughput, waste control issues, and plant modifications that may be required to run a process; and marketing people in terms of the net present value of the product, how much it can sell for, etc.” 

“It is important ….to get stakeholders to develop….agreed-upon objectives of process development.” 

“communication among….personnel is critical during process development.” 

“We need to…. provid[e] development team members with systems or tools to facilitate communications among different disciplines.”

“Unless the manufacturing team is involved in the process development, they will not have confidence in the scale-up”. 

“…manufacturing and commercial input at this stage [late stage discovery] are essential for choosing the optimum processing route”. 

“Team members need to be involved in setting targets for cost, manufacturability, waste and emission loads, development time….” 

“These alternatives must be evaluated based on….criteria agreed upon by all stakeholders….” 

“If stakeholders are involved in planning experiments, it’s likely that more useful data could be collected from fewer experiments.” 

For me, the management tool the authors recommend for achieving this widely held ‘process vision' is Panglossian. 

The authors propose that even at the experimental program level one should try to bring together a diverse project team including representatives all the way out to marketing, frequently enough to work out priorities and make decisions. This is what they recommend. 

This seems excessively optimistic as regards human nature. Instead, I suggest, one could establish a 'process vision' statement establishing some sort of median or normal starting-point performance criteria that would address recurring diverse concerns of process development, manufacturing, regulatory affairs, and marketing and that would chevvy the most common interests of the downstream project teams on the upstream collaborators. In this implementation, the process vision would be via a statement delivered with full corporate authority that would continuously challenge upstream groups with the standard core concerns of the downstream members. 

The authors illustrate marvelously this challenging interaction throughout their article. What I interpret them to be saying is that the problem is not that different elements of the project team have concerns that inevitably seem to operate at cross purposes; but that the team members can reach solutions that satisfy all parties, so long as the areas of tension are discovered early enough. 

KiloMentor has a strong preference for its alternative. The use of a process vision statement as a proxy for the perspectives and concerns of downstream project groups seems preferable to using large frequent group meetings to actually direct even the collection of particular data. For a company’s drug product projects to be successful and on time, any process’s strategy must not conflict too greatly with the psychological needs and private professional goals of the individual team members. The people downstream in the project, whether they be in late-stage process development, manufacturing, or marketing, simply will not give a project the attention it needs until it arrives at the phase where they are being held singly and personally responsible. They are too busy concentrating their attention on what is on their plate already and extinguishing the fat that is already on fire. This is human nature! Besides, pharmaceutical product projects can go on so long that some participants can realistically expect to no longer be involved when a late-stage discovery project limps into manufacturing or marketing. People may hope or plan to outrun the difficulties. Only unambiguous corporate endorsement can get everyone to give a thought to early-stage projects.

Equally problematically, the upstream professionals, working at a particular phase of the work on their own turf, would require an uncommon personal modestly to accept without rancor face-to-face demands that particular questions be answered on a priority basis. 

A corporate ‘process vision’ statement takes the personalities and egos out. At the same time, the standards proposed by a process vision statement would command authority and yet not be carved in stone. They would exist to bring a persistent awareness of particular concerns. They would bring those different needs, which may be pulling at cross purposes to early attention, and they can be expected to bring the affected team members together as needed to create or negotiate a solution. 

Claisen’s Alkali Reagent for Separating Very Weak Acids such as Enols and Cryptophenols

A Cryptophenol

One of the goals of the Kilomentor blog is to reinforce awareness of some of the simple, but robust, methods of isolation which have been used more frequently in the past but that can easily be scaled up.

Claisen’s alkali is made by dissolving 35 g of potassium hydroxide pellets (itself 85% potassium hydroxide and 15% water) in 25 ml of water with vigorous stirring and simultaneous external ice-cooling, followed by dilution with 100 ml of methanol and repeated cooling.  It is necessary to be thorough with the cooling because otherwise the base will probably react with the carbon dioxide in the air and weaken itself.

Claisen’s alkali is a powerful base solution that dissolves organic substrates sufficiently well so that the rate of deprotonation is rapid. At the same time, the liquid is immiscible and unreactive with saturated hydrocarbon solvents. Weak hydrophobic phenols and enols can be extracted out of hydrocarbon solution by contacting them with Claisen’s alkali. Thus, for example, 2,4,6-triallylphenol, which is insoluble in aqueous alkali can be extracted from petroleum ether with Claisen’s alkali. As another example, Vitamin K1 is easily isolated from 3-5% alfalfa concentrate by shaking an alcoholic suspension of the oil with aqueous sodium hydrosulfite to reduce all quinones to the hydroquinone state, then extracting with petroleum ether to take up all the hydrophobic solutes and then extracting this with Claisen’s alkali.  The extract is yellow from the formation of potassium anions and dianions. By dilution of the alcoholic solution with water even without acidification the K1 hydroquinone can be extracted back into ether and isolated from there.  The back extraction into ether works even without acidification because the hydrophobic hydroquinone in aqueous solution hydrolyzes enough to be taken up into ether and this drives the hydrolysis according to Le Chatelier’s Principle.

Lipophilic primary and secondary sulfonamides can also be separated from other substances that lack weakly acid hydrogens using Claisen’s alkali extraction of a pet. ether solution.  The key is that the sulfonamides must be sufficiently large and hydrophobic to dissolve in the pet. ether.

There is no study that I know that teaches what compounds can be taken up in Claisen’s alkali. At the very least it seems that a hydrogen on carbon needs to be activated by at least one carbonyl and one double bond.  In another well-known example exhaustive dichromate oxidation of cholesterol and removal of extensive acidic fractions by a simple aqueous base extraction leaves a mixture of delta 4 cholestene-3,6-dione and several monoketones and other neutral products (Org. Syn. Coll. Vol. 4, 189 (1963)). Repeated extraction of a solution of this mixture in pet. ether with Claisen’s alkali as long as the extracts are colored yellow (note the simple visual test of effectiveness) affords a simple means of isolating the total enedione present, which in this case is 40%.

Compounds which are so weakly acidic that they cannot be extracted by basic aqueous solution but which can be captured into Claisen’s alkali are termed cryptophenols, a descriptive term that is not however widely known or used. Molecules in which a methylene is substituted by two moderately electron-withdrawing groups would be candidates for Claisen’s alkali extraction.

Explaining Process Intensification to Process Chemists

Process Intensification is a concept well known to engineers and essentially unknown to process chemists. This blog will try to narrow that gulf.

In the 1980s, Colin Ramshaw at ICI coined the term “process intensification” to describe his engineer rethink about gas/liquid mass transfer. That resulted in aiming for much smaller chemical plants that would be markedly cheaper and safer than existing ones.

Ramshaw’s thinking assumed no pre-existent equipment. That is to say, he did not devise a process to fit a particular plant’s physical assets. He started thinking afresh.  The most widely publicized outgrowth of such thinking was the high g centrifugal distillation. Distillation he saw as fundamentally a gas-liquid mass transfer for which the key cost drivers for a given system were well established:

·   Well mixed liquid and gas phases

·   Lots of interfacial surface area

·   Thin liquid film

·   Counter-current operation

In general, gases mix well in all conditions as do low viscosity liquids in thin films. Simple geometry teaches us that smaller, finer, packing gives us more surface area so that would be the obvious way to go - a column with very fine packing with counter-current gas flow.

However, a liquid film running through a bed of fine material floods when the film thickness becomes approximately equal to the clearance between the bits of packing.  The limiting factor is the thickness of the liquid film and most of the factors determining film thickness are physical properties of the fluid and are not open to modification.  Only gravity was independent. The higher the applied gravity the thinner the film and the smaller the packing could be. If gravity could be varied that would give a lot of mass transfer surface area for volume i.e. an intensified plant. To increase virtual gravity the centripetal effect of rotating the packing in a “high-g” machine was demonstrated to deliver an order of magnitude reduction in size. The idea was a major announcement at the time. An article appeared in Chemistry & Engineering News, “Novel Separation Technology May Supplant Distillation Towers’March 7, 1983.

Even though the high-g machine never became widely adopted this zero-based engineering that starts afresh from first principles exemplified the essential process of science and had appeal as a creative process. Understanding a process (a reaction, a crystallization etc.) with sufficient depth so that the key rate-controlling steps are understood and then matching that process to the right processor was seen as potentially breakthrough methodology.

Heat exchangers are another example. Obviously one of the keys to performance is heat transfer area so it is surprising that many heat exchangers are based on pipes that have a minimum surface area! It has been proposed that this reflects mechanical engineering considerations rather than process ones. Clearly the plate heat exchanger is a much more effective way of providing area, albeit with some mechanical downsides.

This is diametrically opposed to the normal approach in the chemical and pharmaceutical process industry, which creates a process to match standard equipment. Although there are good economic reasons for this in a batch process industry, there was a desire not to lose sight at the design stage of the possibility that intransigent difficulties operating in the standard way may become trivial with different equipment. For example, the ubiquitous batch reactor might be used to carry out a polymerization in the laboratory but the recipe used on plant scale will be adjusted to match the relatively poor heat transfer performance of a larger reactor. Here, the process has been tuned to match a characteristic of the processor. 

Perchance in some particular instances, the rationale for this matching process may even be lost in corporate history. Perhaps a batch takes a certain length of time to complete because many years ago it was matched to a particular reactor or type of reactor.

Just as important is the corollary that the process that has been matched to a particular processor cannot be simply transferred to a different processor without adjustments. For example, for exothermic reactions rate is proportional to temperature. A reaction temperature is selected so that  the heat can be removed and the reaction condition kept under control. One can make an order of magnitude change in the rate and still dissipate heat by going to a plate reactor. Thus a higher operating temperature can be held in control and a much shorter reaction time becomes practicable. The reaction time may become so short that continuous processing becomes possible. In fact, the new reactor will not “work” unless the process conditions are changed to harmonize with its new character. 

In the above example of an exothermic reaction, the matching of process temperature is key. Other characteristics that might need adjustment are mass transfer, mixing, diffusion, etc. Often the controlling step is obvious, sometimes it is completely unknown and sometimes there are different rate controlling steps during the course of a reaction. What the critical variables are constitutes fundamental understanding.

Batch reactors or in their continuous form continuous stirred reactors (CSTR) will match a process that inherently needs long times (perhaps diffusion controlled with real maximum temperature limitations). Oscillating columns offer moderate residence times with better than batch heat transfer. Plate heat exchanger type reactors (HEX reactors) are a good match for clean high heat transfer duties.  Spinning disc reactors offer good heat and mass transfer as well as good mixing. It is erroneous to claim that one is inherently “better” than another, any more than to claim a Posidrive screwdriver is better than a crosshead. What is required is to match the process and the processor! All the benefits of process matching, precision processing or process intensification are not always obvious. Clearly capital cost saving is the classic rationale with smaller reactors, less civil costs, less safety systems but improvements in yield, higher conversions, less or no solvent use are also important along with energy reduction. Improvements to product properties and even novel products that competitors find difficult to match are other potential major benefits.

As discussed above, the matching of the process to the processor’s capital equipment is key to precision processing. It is also important to recognize that the way a business is run often reflects the physical assets the processor has access to. For example, there is an essential connection between the fact that multiple products are usually synthesized in a batch reactor and such processing is normally conducted in some form of campaign operation because there is a need to clean scrupulously between batches. Again, consequently, a warehouse is usually needed to meet customer delivery demands.

The way the business works is matched to the characteristic of the processor. Change the processor to a low inventory continuous reactor and it might be possible to move to just-in-time (JIT) manufacturing with all those benefits. The business operation has been properly matched to the new processor characteristics.

Process Intensification does not mean the same thing to different authors. For example Aman A. Desai, Erich J. Molitor, and John E. Anderson in Process Intensification via Reaction Telescoping and a Preliminary Cost Model to Rapidly Establish Value, Org. Process Res. & Dev. 2012, 16, 160-165 define 'process intensification' as simply measures which significantly increase the productivity of a chemical process. Since ‘significantly’ is not defined this confuses a useful definition and replaces it with something indistinct. The idea of starting afresh and selecting appropriate engineering and equipment based on the needs of the chemistry without limitations is lost in their redefinition and this concept is worth retaining with its own lexicography.