kilomentor

I received the following comment regarding a recent blog post.

Dear Kilomentor,

I am trying to isolate CF3COAr (80% w/w assay) derivative compound from the ArBr (10% w/w and Piperidine COCF3 derivative (10% w/w) mixture . CF3COAr derivative is low melting solid (mp ~ 52 °C) and I don’t have the distillation data of the same. I just would like to know whether bisulfite adduct isolation can be attempted on 25 kg scale or which method you would suggest. Small scale preparation involves isolation by precipitation in cylcohexane (~ 50 % recovery) at lower temp (- 20 °C). Please suggest me if you have any experience.

Dear Marto,

Certainly the carbonyl of your desired product is electrophilic enough to react with bisulfite! My slight concern is that the trifluoromethyl anion might be displaced in a competing fragmentation reaction. A small scale test would quickly find this out. The conditions will need to be mild. This is an excellent example where isolating an easily reversed derivative should easily remove some substantial impurities. Note that it is not necessary that the bisulfite adduct actually precipitate for the method to work. It is sufficient that the ionic sodium bisulfite salt form and be extracted into an aqueous phase. If an appropriate inert, water-immiscible organic layer is also provided the bromobenzene and the piperidine trifluoroacetamide will remain substantially in the organic layer while the bisulfite adduct is in the water. Separating the liquid phases and acidification breaking the adduct should allow the trifluoroacetophenone to be taken back into a fresh organic layer from which it can be crystallized, precipitated or used directly in a subsequent reaction.

A separate concept can be used to remove the piperidine trifluoroacetamide, if it were somehow to still contaminate your product. It would seem it can be removed from your product mixture by treatment with some aqueous hydrochloric acid with a small amount of acetic acid cosolvent to promote solubility. This tertiary amide is probably rather sensitive to acid catalyzed hydrolysis because of the strong electron withdrawing strength of the trifluoromethyl. Furthermore, both hydrolysis cleavage products, piperidine hydrochloride, trifluoracetic acid as well as the acetic acid cosolvent all go to water. Although trifluoroacetophenone might have some sensitivity to basic fragmentation, it will be untouched by aqueous acid.

Bear in mind always, however, that what is done by way of purification is always dependent upon how you plan to use the product. If the subsequent transformations of your trifluoroacetophenone do not touch the impurities you have, then later separation may be easier or more convenient, or better still, the subsequent reactions may purge them for you. Even an intermediate with a rather low purity, like your 80%, might be practically pure enough, if the impurities don’t use up expensive reagents and don’t produce even more troublesome impurities by reacting further. Bear in mind though when using a low assay intermediate such as yours to do subsequent chemistry that your assay must be accurate because the upcoming stoichiometry will be dependent upon it! 

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

The boiling points of acetic acid and acetic anhydride respectively are 117 and 140 C. Acetic acid is infinitely miscible with water and is an excellent solvent for broad classes of substances. Mixing solutes dissolved in the acid with water leads to decreasing solubility of most organic compounds.

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

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

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

Potentially chloroacetic acid and chloroacetic acid anhydride can be considered for similar usage as acetic acid/acetic anhydride above. A key difference is that the chloroacetic acid esters are more easily hydrolyzed and can even be removed without exposure to either acid or base by treatment with thiourea. 

Do medicinal and pharmaceutical development chemists suffer a greater incidence of cancers than the general population? This is a question for epidemiologists. I don’t know whether the answer is known or not. I suspect from anecdotal data, the answer is that our health is equal to or better than our peers. If this turns out to be so, then this casts serious doubt on the level of concern regarding genotoxic impurities. Let’s admit it. We medicinal and development chemists have come into contact with many compounds that on the basis of structure would be deemed likely genotoxic materials. If a substantial number of them are as dangerous as is claimed, why are we still doing all right healthwise? This isn’t to say we shouldn't take proper precautions, but remember, lots of us were doing chemistry for years before anyone thought about genotoxicity. Just to exemplify the situation in the past, I can vividly remember when I cleaned mercury metal  by wrapping it in a tea towel and squeezing it through into a large funnel using my bare hands!

Distinctively Different Impurities

In developing a process, optimization may proceed to a outcome satisfactory for a particular purpose by only modifying a few of the possible reaction variables.  Yet, in so doing, the situation may sometimes arise that an unidentified impurity can remain persistently and invariantly at a low but still unacceptable level as a contaminant. This occurs when the variables that worked well for optimizing the overall reaction yield and isolation do not purge the impurity. 

When such an impurity has an unknown structure, it is not easy to construct a hypothesis for its formation and thereby predict conditions that could reduce its occurrence.  The usual approach in this situation is to use very sensitive analytic methods, such as HPLC/MS/MS to try to get some indication of the structure and then advance the purification using this knowledge.  Sometimes, however, the apparent impurity concentration will be exaggerated by the analytical method. This occurs in the situation where the detector is much more sensitivity to the impurity than to the desired product. The impurity can then be present at lower concentrations  than it appears from the analysis. This occurs in HPLC with UV detection for example when the impurity has very much the stronger absorption at the detecting wavelength.  Even though the actual impurity concentration may in fact be low enough to be innocuous for regulation purposes, because the compound is structurally unknown, one cannot prove to regulatory authorities that the impurity is at that low and acceptable level without identifying it.

Rather than processing large amounts of product using laborious treatments to obtain a concentrated crude sample of unknown for standard preparative chromatographic separation, Kilomentor has found that a further investigation of the synthetic reaction using statistical design methods to test the influence of some of the previously unchecked reaction variables can often quickly provide a solution to this problem. The solution arises from either of two outcomes. Investigating the new parameters, while holding the previously optimized parameters at their optimized levels, can often produce a condition where the proportion of the impurity in the product is significantly changed. If this leads to new conditions that are still acceptable with respect to yield and that reduce the level of this impurity below the level of concern, then the impurity can be left unknown. This is an easily understand strategy and outcome. It is the second possibility however that makes the investigation more likely to solve the difficulty. In the alternative but less frequently imagined outcome, the investigation of the effect of new parameters leads to conditions that very substantially increase the amount of the unknown impurity. But this also is a useful result! Now using these conditions, useful amounts of the unknown can be much more readily prepared.  These larger amounts are more easily separated, purified, and the substance identified using standard methods. With the structure now available and with parameter(s) that affect the concentration of the substance known, controlling the purity level is well on the way to being solved.

As has been mentioned above, the impurity of concern in this scenario is usually much more sensitive than the desired product to the mode of detection. It logically follows that most often such impurity has a structure quite different from the product itself.  Thus the impurity is unlikely to be a diastereoisomer or a geometric isomer of the product.  The more common sources of such quite different impurities is a distinctly different substance that is an impurity in one of the immediate starting materials of the product. A common cause of these impurities is local concentration effects related to stirring inefficiencies  or variations in the ratios of reactants and products during their combination in the synthesis.

Distinctively Similar Impurities

Impurities that are very similar in structure to the desired compound are a quite different situation. Most often these arise from other impurities already present in the starting materials; particularly homologs and isomers of the purchased starting substances. These usually have almost the same sensitivity to a detector as the desired product so the estimate of their amount is usually good but they are the most difficult to purge by changing reaction conditions and the most likely to become trapped and to co-crystallize with the product. These impurities are most easily identified and purged by purifying the starting materials that typically are much smaller molecules. Nevertheless, process chemists need to constantly keep in mind that it is a great waste to spend resources performing a purification if the later steps in the process sequence themselves provide means to keep the impurity or the impurities derived by its transformation out of the final product. This automatic purification provided by the processing itself is commonly called purging. It is difficult however to distinguish between an impurity that is remove by subsequent processing and the impurity that is further transformed in parallel and is carried along becoming impossible to detect analytically as it is further transformed.

Kilomentor wishes readers a joyous Christmas and a healthy, interesting and profitable New Year 2013. I will be away from my books for a good part of the winter in Sourheast Asia avoiding the Canadian snow. Although I may continue to write the reference work won't be up to standard.

My project is to read through many of the old articles published in Organic Process Research & Development since I can access them on line. We'll see what I come up with.

Best wishes
Clarke Slemon
THE kILOMENTOR

Kilomentor has written about the selective reactivity of one among several of the same functional groups within a chemical structure at

Larry Fertel asks a question about his Friedel Craft reaction at the

Organic Process Research & Development Networking Group on LinkedIn.

Larry wrote, “I am running a classical F-C reaction based on a process given to us from our customer: benzene derivative, benzoyl chloride (1.1 eq.), AlCl3 (1.1 eq), nitrobenzene solvent, 85 deg C, . i.e standard conditions. When I cool and quench into water and HCl or add water/HCl to the reaction, I am supposed to see 2 layers, then separate the aqueous and go forward with the isolation of the product in the organic layer, etc..

Instead, after the exotherm of quenching, I get massive amounts of solids, the stirrer jams, etc... a real mess. The solids are presumably Al salts, I don't see the nitrobenzene sitting in the flask, it seems to be incorporated into the solids. Note that the reaction goes to completion, no s.m. is seen at all. Is there a "standard" recipe for the workup for this reaction to avoid formation of solids. Note that the customer received the process from their previous manufacturer who is loath to give more details. Also, no time or money to investigate other methods, catalysts, etc..”

From Larry’s description of the reaction methodology I assume the following:

1. The reaction mixture is homogeneous at the end of the heating period. {I assume this because aluminum chloride forms a soluble complex with nitrobenzene. This is the reason for its popularity in F-C reactions. Otherwise it is not a particularly practical solvent since it is high boiling and is usually removed in the end by steam distillation.}

2. When you cool the reaction mixture before quenching it is not a mess yet.

3. You are adding the aqueous HCl into the nitrobenzene solution or slurry. {I assume this because otherwise you would probably have described what happens when a small amount of the quench solution is added, and a little more and so on, with the mixture getting thicker and thicker.}

Larry does not mention details of how he was instructed to do this quench or to what temperature the reaction contents were initially cooled. I think it is very important to keep the reaction mixture very cold during the quench. In fact it is for this reason that a mixture of water/ice and HCl is so often used. Reaction mixtures often thicken so much that wall cooling is probably most often going to be inadequate. If the quenching mixture overheats some hydrolysis of the aluminum chloride to an aluminum hydroxide gel is likely to occur. This I am guessing is giving the mess you report.

Put another way that is to say, it is very important that the solution of aluminum chloride hexahydrate that forms not get warm because the chlorine atoms can be replaced by hydroxyls to give trihydroxyaluminum, which is a gel.

Wikipedia teaching seems to confirm this analysis when it states: “Aluminum chloride is hygroscopic, having a very pronounced affinity for water. It fumes in moist air and hisses when mixed with liquid water as the Cl- ions are displaced with H2O molecules in the lattice to form the hexahydrate AlCl3·6H2O (also white to yellowish in color). The anhydrous phase cannot be regained on heating as HCl is lost leaving aluminum hydroxide or alumina (aluminum oxide) (my italics):

Al(H2O)6Cl3 → Al(OH)3 + 3 HCl + 3 H2O”

Looking for a standard Friedel-Craft acylation reaction with nitrobenzene as solvent, I found the synthesis of methyl naphthyl ketone in Organic Vogel [ATextbook of Practical Organic Chemistry , Vogel, Third Edition, Longmans, pg. 731].
In their procedure HCl is driven off by reducing the internal pressure rather than heating to 85 C as Larry does. The quench is with “an excess of crushed ice”. This suggests to me that so long as the temperature is controlled no additional hydrogen chloride is required although it doesn’t hurt but and reaction mixture must be mixed together with a consistent excess of ice. This is not do-able at scale because adding solid ice cannot be done quickly enough if at all. The quench of the mixture into an excess of ice and enough water to make it stirrable seems a better bet.

I am assume that Larry’s product is soluble in nitrobenzene since the procedure you have been given separates the phases and isolates the product from the nitrobenzene. Probably increasing the amount of nitrobenzene a bit until a solution is worked out will make the experimentation easier. Then when one has something more workable reduce the nitrobenzene back.

Mahendar Velpuri recently asked  in the Custom Organic Synthesis and Process Chemistry Forum on LinkedIn
http://www.linkedin.com/groupItem?view=&gid=1061737&type=member&item=181862674&qid=5a7a2e3c-b873-4179-b40f-be79d4205731&trk=group_most_popular-0-b-ttl&goback=%2Egmp_1061737

  how to remove dimethylsulfide from an organic oily compound when he had already tried column purification and solvent stripping.

There were what I think simpler suggestions than Kilomentor’s but the question reminded me that a blog could be written about the method of separating sulphur containing from non-sulphur containing compounds that I was invoking, since it could be applied to a range of situations and it seems never to have resurfaced in the literature since that first reference in the 60s.
In 1964, G.M.Badger, N. Kowanko and W.H. F. Sasse submitted a short communication  to J. Chromatog. 13, (1964) 234 titled, Chromatography on a column of Raney cobalt.
The small experimental read as follows:

“The freshly prepared Raney cobalt (ca 7.5 g) was mixed with clean sand and packed into a chromatofraphic column (1.2 cm X 10 cm.). A mixture of isoeugenol (0.5 g) and 2,5-dimethylthiophene (0.5 g) was applied to the column and eluted with methanol ( a 3-ft head of liquid was required). Evaporation of the first fraction 930 ml) gave sulfur-free isoeugenol (0.477 g). Subsequent fractions contained only trace amounts of isoeugenol and were also sulfur-free. The dimethylthiophene was subsequently recovered by Soxhlet extraction of the cobalt with methanol.” (my italics).

The discussion pointed out that active cobalt metal binds sulfur containing compounds by chemisorption. However, unlike Raney nickel cobalt has a much reduced tendency to desulfurize material. Nevertheless, this binding is powerful,much stronger than simple adsorption, as the rigorous conditions described for removing the dimethylthiophene from the solid phase attested.

What this suggested to me was that the method would not need to be conducted as a column chromatography. It would probably work simply by stirring the solid with a solution containing the sulfurous material, filtering through filter aid, and washing. Thus the method could separate sulfur- containing from sulfur-free materials by filtration as easily as an insoluble polymer is separated from a solution.

That  desulfurization under the conditions of a separation is unlikely is further suggested by another paper [1960] by the same authors which contains the sentence “Desulphurisation with Raney cobalt was similar to that with W7-J Raney nickel in that, although little reaction occurred in boiling methanol, it was complete in diethyl phthalate at 220.”

It would seem that, besides obviously being able to separate the sulfur containing from sulfur free compounds, the technology should be adaptable to separate compounds that have been derivatized with a sulfur containing reagent from compounds without such appendage.

It might be that the method of recovery of the chemisorbed compound could be improved. Eluting with a solvent containing carbon disulfide or COS might speed the recovery without ireversible contaminating the eluting solvent.

Also a chemisorbant simpler to prepare than Raney cobalt might be available by reducing a cobalt salt with sodium borohydride to give a cobalt boride analogous to the Nickel boride catalysts called P-1 and P-2 developed by H. C.Brown et al.

I have a confession to make at the very outset of this blog article. I have never performed a transfer hydrogenation in my entire career, even though I have been involved developing many hydrogenation process steps using hydrogen gas, often under pressure. How can this have transpired if transfer hydrogenation is better known to process chemists and if it provides all the benefits that I shall recite; benefits substantiated by the many transfer hydrogenations reported in process chemistry books and journals? The reason is perhaps that, once a site commits to having hydrogen handling technology as the companies I worked for had,  using it may be important to justify that expenditure.

 Certainly, catalytic reduction by the addition of hydrogen is a very convenient and atom efficient reaction step. The reagent, hydrogen, is easily removed even though used in large excess and an excess that drives reactions involving it to completion. Another important point to bear in mind is that hydrogenations are often mass transfer limited; that is, the rate of reaction is determined by how quickly hydrogen can be delivered to the surface of the catalyst rather how fast it will react with the substrate. Thus the reaction is often dependent upon the effectiveness of the stirring, which in turn affects the size and number  of hydrogen bubbles created in the solvent mixture. Where it exists this dependency presents a particular concern as the process step is scaled up and the reactor equipment varied.

Transfer hydrogenation is here discussed as it relates to scaling up a hydrogenation step. Chemists who are more accustomed to working in the laboratory are overwhelmingly more familiar with reactions with hydrogen in the presence of a catalyst and much less with the transfer of hydrogen atoms from a donor reagent to a substrate under catalysis. Yet this latter, transfer hydrogenation, is cheaper and safer both because no free hydrogen is used and because it does not require a special reactor, special stirring, or special gas handling auxiliaries. Indeed, the benefits of transfer hydrogenation  seem to be well understood by seasoned process chemists from the evidence of descriptions in process chemistry monographs but still far  too unfamiliar to new graduates, university scientists, and discovery chemists.

Particularly surprising is that transfer hydrogenation has not been adopted more in academia particularly for undergraduate research since transfer hydrogenations are both safer and easier to sample for reaction completion. There is no flammable gaseous headspace and since there is no pressure sampling can be done with a septum and syringe needle. Indeed, essentially no free divalent hydrogen is present at any time during the reaction. Furthermore,  unlike the reaction using hydrogen gas, it is not mass transfer limited by the rate the gas gets stirred into the solution. Thus, the reaction kinetics can be expected to be simpler.

 As early as 1973 Chemical Reviews wrote “Certainly these catalytic
transfer reductions at the very least are a considerable technical improvement over the rather messy traditional reduction with metals and acid. The catalytic transfer reactions appear to be more selective than regular catalytic hydrogenation…… There is no question as to the greater experimental convenience with catalytic transfer hydrogenation, most reactions being complete after 1 or 2 hr at reflux, without the use of elaborate apparatus. It is surprising that routine use is not made of this process.”
 
Although the use of hydrogen gas is more atom economic if one bases the decision naively  on the simple balanced equation, in practice a large excess of hydrogen is normally used as an atmosphere in the headspace. Also, the reactor is routinely repeatedly degassed, flushed, and vented to start, and all the excess hydrogen is lost when the step is worked up. With transfer hydrogenation, the hydrogen source is typically used in only a 4-5 times molar excess and these hydrogen sources are cheap and do not present any particular waste problems.

Vigorous boiling of reaction mixtures promotes the reaction rather and does not expel hydrogen.  The catalyst makes possible transfer of hydrogen atoms from  a suitable donor to a suitable substrate without hydrogen release making transfer hydrogenation compatible with any inerted plant reactor. There is no special venting requirement and no fire or explosion hazard and these advantages result in significant cost savings and flexibility of operations.

Since transfer hydrogenation most often use relatively expensive supported palladium catalyst, an important consideration is whether the hydrogenation using molecular hydrogen or the transfer hydrogenation using a donor  results in the higher catalyst expense. I can find no generalized finding comparing the methods on economic issue. A related question is whether there is any increased or decreased tendency for traces of noble metal catalyst to be trapped in the isolated products using or the other of the two methodologies. Again this would be important because a disadvantage of catalytic hydrogenation in all its forms is the risk of residues of toxic heavy metals that can tenaciously adhere to the isolated product. From what I have seen of the literature this difficulty is neither reduced or enhanced using transfer hydrogenation.
 
Although other useful reviews have been devoted to transfer hydrogenation these have not been from the perspective of scale-up advantages. I have seen little that answers the general question of what makes a hydrogenation convertible to transfer hydrogenation and how one might predict situations where it is unlikely to work? A tentative rule might be that if the hydrogenation cannot be done using either palladium or a soluble catalyst it is has a reduced likelihood to work with transfer hydrogenation.

Hydrogen donors include cyclic ethers, benzyl alcohol, cyclohexanone, 2-propanol, ethylene glycol, 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, cyclohexene, cyclohexadiene, limonene, hydrazine, ammonium formate, ammonium hypophosphite.
Takeshi Nishiguchi, Hideaki Imai, Yoshikazu Hirose, and Kazuo Fukuzumi in  Journal of Catalysis, Volume 41, Issue 2, February 1976, Pages 249–257 report the hydrogen-donating ability of organic compounds in the hydrogen transfer reaction catalyzed by Pd-carbon decreasing in the order: indoline > formic acid > tetrahydroquinoline > piperidine > pyrrolidine > cyclohexene > N-methylpyrrolidine > di-n-propylamine > d,l-limonene > 1,2-dihydronaphthalene.

Cyclohexene and cyclohexadiene both produce benzene as co-product and so might be discouraging just to completely avoid the slightest health exposure question. Isopropanol is sufficiently volatile to be easily removed along with acetone produced. The heterocyclic compounds as well as their aromatic heterocyclic products can be removed by acid extraction of the reaction mixture making workup easier in the cases of neutral or acidic products. Hydrazine can be washed out and its oxidation product is a gas. The inorganic ammonium salts are also water soluble and the co-products are volatile. These formats are also the most active. Limonene which is said to be a good hydrogen source gives rise to by-product and co-product that are not always easily removed.

It would appear that the most convenient hydrogen atom source of all for transfer hydrogenations is ammonium formate. Unlike the organic molecules that can donate hydrogen it can easily be removed from the product either by washing with water or evaporation. Ammonium formate is completely and easily volatile. Ammonium formate is reported to be soluble in water, formic acid, acetic acid, methanol and somewhat surprisingly ethyl ether and apparently THF can be used as a cosolvent with methanol in these reactions. Sodium hypophosphie is another inorganic source of hydrogen atoms for reduction. The transfer hydrogenation can also be done by dissolving the substrate in ethanol, adding the 10% Pd/C, heating to the reaction temperature and adding an aqueous solution of sodium hypophosphite to the stirred solution. Sodium hypophosphite is reported to be soluble even in cold (ethyl?) alcohol.

Reduced pressure is typically created using a vacuum pump attached to an otherwise leak-proof system.. This setup operates by sucking the gases in the closed reaction volume through a one-way valve. To the extent that the ‘closed’ system leaks, this pumping needs to be continued throughout whatever chemical operation is conducted, since more atmospheric gas will diffuse into the ‘closed’ system.  Molecules from the liquid and/or solid constituents of the reacting system are not part of the ‘atmosphere’ although under ideal non-leaking conditions and perfect evacuation they will be the only gaseous elements present. It is by condensing the volatile elements of the reaction mixture that evaporating or distilling separations occur.

Normally it is the mixture of gases found in standard air that leaks into the evacuated vacuum gradually damaging the pressure reduction.  When a controlled leak through a glass capillary is used to prevent bumping during distillation, the sparging gas can be whatever the experimentalist chooses to flow into the top of that capillary. Since the still pot contents are usually quite hot during distillation, an inert, oxygen-free gas is favored to prevent oxidative degradation in the hot vigorous boiling zone. When the still pot contains basic amine functionalities, the leak preferably does not contain carbon dioxide which would react with that substrate to give carbamate salts.

Using a vacuum pump is not the only means to create a vacuum. Another method to get low pressures in the laboratory is by using the water pump, carbon dioxide, and potassium hydroxide. [F. Krafft, Ber., 37, 95 (1904).] The system is first exhausted with the water pump and then filled with carbon dioxide gas. This process of exhaustion and filling is repeated four times, after which the apparatus is sealed off, and a stop-cock, which connects to a bulb, containing 50 per cent potassium hydroxide solution is opened. The carbon dioxide is absorbed, and the vapor pressure of water is reduced by first cooling with ice and then carbon dioxide snow. The bulb is then sealed off above the stopcock and the distillation carried out in a closed system. Krafft claimed he could obtain a vacuum low enough to produce the green cathode rays in an electric discharge within 15 to 30 minutes even in large containers.

This use of concentrated aq. KOH solution to irreversibly react with carbon dioxide could be combined with carbon dioxide sparging to make reduction in pressure more efficient. If the above distillation apparatus, including the 50% KOH solution attached to the reaction vessel, were placed in a glove box or glove bag with a carbon dioxide atmosphere so that any gas leaking into the system is just carbon dioxide, then the system should be maintained at low pressure even if it leaks slightly because the leaked gas will also be removed into the alkaline liquid.

Obtaining very low pressures near the liquid surface where evaporative distillation is desired is particularly difficult on scale. Perhaps supplementing the stand high vacuum pump with some such carbon dioxide trapping technique would work. I don’t know.

 If the controlled leak is a large supply of super-heated water vapor, the pressure will be only the vapor pressure of the gaseous water plus whatever vapors come from the reaction mixture. This might lead to a reduced pressure steam distillation.

 At the Current Process Chemistry Conference put on by Cambridge Healthtech Institute in Princeton, June 13-14^th , Mathew Truppo, Process Chemistry Merck & Company, gave a talk about the application of immobilized enzymes to synthesis using the example of the synthesis of the diabetes II drug Januvia (sitagliptin). The use of immobilization allowed the enzymes to be recovered and recycled efficiently and cost effectively. Because the enzymes were easily separated this meant that complicated separation procedures forremoving denatured enzymatic  protein from the product were avoided. Because the process was conducted by flowing the reactants past an immobilized plug of enzyme, trapped water phase, and coenzyme there was no need to do a water rich/organic rich phase separation or the disposal of the water-rich phase. Enzyme and coenzyme were immobilized within a solid with structured pores that contained the aqueous fluid.

Sitagliptin is a tertiary amide with a beta amino. It has a single centre of chiralty at the amino bearing carbon. It is produced by  stereoselective reductive amination of the beta ketone. Dr. Truppo did not detail the particular immobilization used in this case but from the slides it appeared that the enzyme along with a small portion of its aqueous environment was trapped in some geometrically regular solid pore structure. Cofactors were involved in the transformation and it was stated or implied that these cofactors were also trapped in the immobilizing system. He stated that getting and maintaining the correct water content was very important. Isopropyl amine was continuously supplied in the reactant stream. Acetone the co-product was continuously removed from the system.

This Sitagliptin talk  from Dr. Truppo blended with another presentation by Dr. Chris Savile of Codexis pertaining to Codexis’s progress developing a systematic methodology for the evolution of improved catalysts. Both presenters made it clear that now one could afford to use immobilized enzymes from the very earliest stages of development all the way to commercialization, because a client only needed to pay for incremental improvements in the enzyme as one moved a project forward. That is to say, at the very early stages a company like Codexis could provide an enzyme off the shelf, at competitive cost, that could produce small amounts of material; then, when kilograms were needed, the enzyme specialist would perform more optimization  to take the enzyme improvement to a stage where it could supply that need; and finally, if the process moved through the clinic into manufacture, another round of refinement could be performed to really optimize the enzyme for full production. Thus one would only need to pay an enzyme specialist collaborator to produce a fit-for-purpose enzyme, and not suffer a fully optimized, full price cost even for candidates that fail as drugs.

Both speakers made the point that one of the areas of cost saving was that with immobilized enzyme processes in a flow system, scaling up was much more predictable. For transformations where many variants of enzyme are available in bulk synthetic chemists should now think first about the possibility to use these enzymes.

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• Continuous Chemical Flow Reactors that Scale so Well are not New
• Using the Bisulfite Adduct for Purification at Scale: Practical Purity and Purging of Impurities by the Process Steps
• The Potential Use of Acetic Acid and Acetic Anhydride for performing Solvent Switches during Work-Ups
• A Question about Genotoxic Impurities
• Improving the Purity of Product from a Good-Enough Process
• The Problem of Oiling Out in Chemical Process Development
• Christmas and New Years Greetings
• Selective Silyl Group Protection: A Possible Preparation for Scalable Extractive Separations using Acetonitrile and Hexane Phases
• Friedel Craft Work Up of Aluminum Chloride catalyzed Reaction At Scale
• Removal of Hydroxyl Impurities from a Solid Product at Scale
• Separating Sulphur-containing from Sulphur-free Compounds both in the Lab and At Scale
• The Relationship between the Risk of Catastrophic Failure and the Size of the Scale Up Steps in Chemical Process Development
• The Advantages of Transfer Hydrogenation for Chemical Process Scale Up
• Distillation with Reduced Pressure using Carbon Dioxide Atmosphere to Create Enhanced Vacuum
• Reactions on Immobilized Enzymes can Telescope Process Steps, Eliminate Isolations and Reduce Costs at All Stages of Pharmaceutical Development

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