kilomentor

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 zero-based thinking moved away from existing equipment. He started thinking afresh. Distillation for example he saw as fundamentally a gas liquid mass transfer for which the key cost drivers for a given system were well established:

1. · Well mixed liquid and gas phases
2. · Lots of interfacial surface area
3. · Thin liquid film
4. · 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, but the high-g machine never became popular.

Even so, this zero-based engineering that starts afresh from first principles exemplied the essential process of science and had appeal as a creative process. Understanding a process (a reaction, a crystallisation 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 innovation.

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 180 degrees 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 feeling 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 polymerisation 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 instance, 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 corrollary 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 disipate 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, anymore 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 is key to precision processing. It is also important to recognise that the way a business is run often reflects the processor. For example multi products on a batch reactor with the need to clean between batches usually means some form of campaign operation of the reactor and a warehouse is 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.

Kilomentor has suggested in other blog entries, that process chemists think ahead of time about possible impurities that could contaminate their products arising from impurities in starting material when these impurities are unlikely to be removed by the downstream reactions or process step separations.

An example of such technology has appeared in a US patent application, US2005/0250961A1, authored by Muddasani Pulla Reddy, The application has since lapsed. The invention teaches methods for performing the Friedel-Craft reaction between glutaric anhydride and fluorobenzene catalyzed by aluminum chloride, so that even when standard commercial fluorobenzene containing 300-700 ppm of benzene is used as starting material, the isolated product will contain less than 0.05% of the unfluorinated, 4-benzoylbutyric acid as impurity in 4-(4-fluorobenzoyl)butyric acid. This 4-(4-fluorobenzoyl)butyric acid is an important intermediate for some syntheses of the medicine ezetimibe.

The full disclosure does not explain how or why the procedures taught decrease the amount of the defluorinated impurity. The document in fact does not provide a comparative example of 4-(4-fluorobenzoyl)butyric acid made according to the prior art literature that shows clearly by contrast the improvement taught. All that is said is that benzene is about 5 times more reactive than fluorobenzene to Friedel-Craft acylation. The teaching does not describe how the benzene reacts, what product the benzene forms or what stage in the process the impurity(ies) is(are) removed.

The requirement of a halogenated solvent such as methylene chloride or dichloroethane suggests to Kilomentor that the halogenated alkane solvent may react selectively with the benzene producing products that are more easily removed in one or more of the isolation steps. It appears that in each of the patent documents specific examples one-half the fluorobenzene is mixed with aluminum chloride and halogenated solvent before adding glutaric anhydride. In this mixing period before glutaric acid is introduced, the benzene impurity could have reacted with chloroalkane solvent catalyzed by the aluminum chloride.

The Kilomentor philosophy or strategy of process development ranks processes not only by the number of reaction steps and their anticipated approximate yields but additionally and with higher priority by the anticipated simplicity of the reaction work-ups and purifications expectd as part of the process step. A proposed ranking system for isolations is provided in an earlier Kilomentor blog. A consequence of this selection principle is that process steps which involve phase switching as taught be Curran tend to be preferred over steps in which starting materials, by-products, and co-products are not so easily separated. In particular, intermediates that are carboxylic acids or amines and that can be separated by acid-base extractions are preferred intermediates as contrasted to neutral intermediate substances.

The same philosophy is taught by Jun-ichi Yoshida, Kenichiro Itami and coworkers in their article, Chem. Rev. 2002, 102, 3693-3716, Tag Strategy for Separation and Recovery. The key difference is that these authors are thinking about tagging products, reagents or by-products to simplify the separation in a process that has already been chosen and is just being optimized. In contrast, Kilomentor would be making the choice among different proposed paper syntheses based, to a fundamental extent, upon whether the intermediates in the process steps are easily separable because they are naturally ‘tagged’ by the functional groups they bear. These naturally tagged intermediates are those intermediates containing (most frequently) acidic and basic functional groups which enable simple acid-base extraction separations. Put another way, Kilomentor uses the concept of phase tags to select a preferred route, while Yoshida teaches the contribution tagging can make to improving the ease of separation in a previously selected route. Also, while Yoshida’s review encompasses phase tags that are contained within or can be attached to, any one of reagents, co-products and by-products and not just the desired products, Kilomentor only looks at whether the desired intermediates themselves contain or could contain some tag.

Yoshida sees tags as being similar modus operandi to protecting groups. Typically a protecting group is introduced into a molecule in one step, protects its corresponding functional group during some transformation(s) and then is removed in still another step. The protecting group protects a function group from undesired reaction. A tag is introduced intentionally before a process step, simplifies the isolation of pure product from the step and is subsequently removed. The tag is not an inherent part of the process but a functional add-on. Yoshida does not completely ignore the kind of tagging Kilomentor recommends but calls it the masking of tags. To quote:

“Another approach to this issue is masking of tags (Scheme 7). In some cases, tags are masked so that tagged molecules retain their natural phase affinity. Thus reactions can be conducted under homogeneous conditions in organic solvents. After the reaction, however, the tag is converted into its active form to effect separation of the tagged molecule from untagged molecules. A typical example of this case is acid/base extraction. For example, an ammonium ion tag is unmasked by protonation of the corresponding amine tag and the tagged compound is extracted from the organic phase into acidic aqueous phase. Remasking the tag by neutralization enables reextraction of the tagged compound into the organic phase (phase switching). In such a case, the tag is not a simple tag, but a phase–trafficking tag or “phase shuttle” because it facilitiates the back and forth movement of molecules from one phase to another.”

One of the non-obvious outcomes of structural identification using spectroscopy (particularly NMR and MS) is the decrease in experience with distillation, among organic synthetic chemists. Because even an inexperienced student researcher can now routinely identify a substance using milligrams of pure compound, flash chromatography high performance liquid chromatography or preparative gas chromatography can replace old-fashioned distillation for making samples for identification in most steps in a laboratory. Corroborating evidence of this trend is the virtual disappearance of boiling point as part of physical characterization in the chemical literature.

Finally, as the catalogues of suppliers of chemical intermediates become thicker, more of the early steps in syntheses can simply be purchased. It is these lower molecular weight entities that used to be prepared and distilled in the lab.

Standard distillation has an inherent problem that became further reason to abandon this technology in the laboratory. Unless a distillation column receives an input of heat that at small scale is usually supplied by vigorously boiling the liquid mixture in the still pot It cannot achieved liquid-vapour equilibrium. Thus on the lab scale, there is hold-up of distillate that is inevitably lost and this can be up to about 30%. Compounding this inherent difficulty is the annoyance that all glass laboratory distillation equipment is expensive and does not easily accommodate the particular amount of crude that you may have. That is, the amount of crude distillate must be selected to fit the size of the physical assembly that you have and not the other way round. Fractional distillation assemblies are not available in your lab drawer in 100 ml, 200ml, 500ml, 1 L 5L and 15L sizes, like round bottom flasks are!

The days when distillation units were patched together with hardened cork or rubber stoppers between pieces of blown glass are long past. Now all glass assemblies are a single piece or pieces joined with ground glass joints. Because of this, now more than ever, distillation assemblies for vacuum distillation often use the same equipment as for simple distillation and don’t appreciate the special requirements imposed by the low-pressure condition.

The boiling point of the fluid mixture in the still pot of a distilling assembly depends upon the pressure at the surface of the liquid, not the pressure recorded on a pressure gauge, which may be and usually is, closer to the vacuum pump.

For pressures from 760 mm down to 15 mm of mercury, a regular distillation flask is satisfactory. For pressures below this level, and particularly pressures 2 mm or less, the diameter and location of the vapour port linking the distillation portion of the apparatus to the condensing portion becomes very important. This is not usually understood.

The increment in vapour pressure at the surface of the boiling liquid, over and above the vacuum pressure reading taken at the receiver is proportional to the length and inversely proportional to the fourth power of the diameter in centimetres of that side arm plus any other narrow portion of the path between still pot and condenser.

As Hickman, inventor of a famous low pressure still, pointed out many years ago, an experimenter may go to great lengths to produce a vacuum less than 1 micron, yet fail to benefit properly from his/her efforts because the pressure necessary to drive vapours from the distilling through neck and side arm is from 1 to 4 mm. The factor limiting te available vacuum is often the distilling assembly shape not the quality of the vacuum pump or vacuum pump oil. Take for example a vacuum distillation using a Liebig condenser attached by a ground glass joint to a simple distillation flask. A Liebig condenser has a narrow bore tube running inside a wide bore tube that serves to supply condenser water to the outside of the narrow bore tube. The vacuum is applied through the length of the condenser down the height of the distilling flask and column to the boiling liquid surface. Because the Liebig condenser tube is both long and narrow, it must add a large pressure to the reading of the vacuum guage at the receiver. Low pressure distillation is impossible.

Bumping from super-heating of the still pot liquid is a great time waster and many solutions have been offered. When distilling at atmospheric pressure boiling chips can be used or a bleed from a glass capillary but the former fails under vacuum and the latter adds to the pressure and is really co-distillation with the gas being bubbled. A very old but effective solution is to place glass wool into the flask so that it is partly above the liquid surface. Using this method magnetic stirring is not possible and an oil bath is the preferred source of heat to avoid over-heating at the flask wall. When using ground glass jointed flask the glass wool must be inserted carefully to make sure that no wool strands get trapped on the ground glass joint where it will destroy the vacuum seal.

When magnetic stirring is used anti bumping is usually not needed unless the stirring fails.

When performing a fractional distillation in a packed column some people do not realize the importance of a near perfect vertical positioning of the column above the flask. Fractionation is achieved by the equilibration of rising vapours and the descending liquid film and that equilibration is a function of the surface area and thickness of that film. If the column is tilted the returning liquid is not spread over all the walls and packing and where it does run it is in a thicker less effective layer. In a tilted fractionating column the height equivalent of a theoretical plate is longer so there is less rectification.

I have seen a large increase in traffic to this blog after I reviewed the titles of some articles from April 2007 to September 2007. Therefore, I continue with this updating.

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

The Use of Mesityl Oxide as a Dehydrating Agent by the Chemical Reaction of Water catalyzed by Primary Amines

Extraction and Phase Switching Hydrolysis-Purifying Phenols.

Avoiding the Impurity from Hell:(chemical process development; purification of organic chemicals; process optimization; impurity identification in organic synthesis)

Reactions “On Water” (immiscible water makes a great heat sink)

Kilomentor moves the discussion from Steam Distillation to other Co-distillations

Polymorphism in Organic Syntheses, Process Development and Formulation

Inverted Filtration: A chemical synthesis laboratory technique particularly helpful at 5-10 litre scales.

Recovering More Product by Crystallization in Organic Synthesis:Trituration with a modified water phase as a potential Chemical Process Development Method

The Complete Blog for the Preparation of Pharmaceutical Salts

Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.

Another Way to Separate Phenolics by Crystallizing of Co-crystals?

Green /Recyclable Solvents: Low Vapour pressure compositions for storage and recycling of solvents that are highly volatile or gaseous at room temperature

Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.

The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt (the choice of salt is not as broad as you think)

Pamoates or Embonates: crystalline Pharmaceutical Salts or Derivatives for Isolation and Purification

Biocatalytic Methods of Enantioselective Synthesis in Pharmaceutical Process Development

Separation by Substantial Differences in Chemical Reactivity of the Same Nominal Functional Group.

Reently Amelia sent Kilomentor a question. She wrote:

Hi, I would like to know what is a good method to remove DMF from my compound. My compound is very polar (with acid and 2 phenol groups)and might not be very soluble in ether. As the compound is a sticky solid, I suspect a tiny amount of DMF is trapped in the solid as I tried freeze-dry vacuum and passing through silica gel column. Do you have a good idea? Thanks.

It is always more difficult to recommend a purification strategy without knowing the full structure. At the same time there is usually good reason for confidentiality.

You say, Amelia, that you think your compound might be insoluble in diethyl ether. If so then triturating with such antisolvent could be an excellent method to remove traces of DMF if present. DMF is miscible with diethyl ether so if your product is essentially insoluble the separation could be excellent and it would certainly be simple and rugged. If too much of your product is dissolved a mixture of ether and hexanewould further reduce the solubility of the diphenolic acid.

Another off the wall idea is from the Kilomentor article “Another Way to Separate Phenolics by Crystallizing of Co-crystals?” 21 March, 2008. Carboxylic acids that are also phenols might be expected for structural reasons to form quite insoluble co-crystals from dry dioxane. The article points out an exception that ortho hydroxy benzoic acids would not be expected to work.

Yet again, if the DMF is tightly complexed to your compound and this is suggested by the failure of freeze drying and passing it through a silica column you might need to make a hydrophobic derivative in order to remove the hydrogen bonds of that hypothetical complex. Complete silylation of your compound would attach at least three trimethylsilyl groups. The derivative would become more and could become soluble in hydrocarbon solvents. Hexane and acetonitrile are immiscible phases and DMF would I think prefer to be in the nitrille phase while your persilylated product may now prefer the hydrocarbon. Kilomentor has written an article about catalysts for quick persilylations and hydrolysis back to product would be facile.

Finally, if your compound is soluble in benzene, you might try adding some sodium iodide to a solution in benzene or other similar solvent. in J. Am. Chem. Soc. 82, 2895 (1960) it is reported in footnote a of Table III that DMF and sodium iodide form an insoluble complex from benzene in a molecule ratio of 1:3! I do not know whether this is actually true and I have never tried this so I would test it out with some DMF in benzene but none of your compound first.

Maximizing chemical yield by recycling mother liquors from crystallizations is underutilized in chemical and pharmaceutical processing, particularly outside the developing world. One of the few articles on this subject is Alan A.Smiths, A Model for Mother Liquor Recycle in Batch Processing, Org. Process Research & Development 1997, 1, 165-167.

Kilomentors discussion here is indebted to this paper.

When crystallizing or recrystallizing product (i) from a reaction mixture, r (ii) a partially treated work up solution, or (iii) from a crude solid isolate, none of the impurities’ concentrations exceeds their solubility product in the solution. That is, more of each impurity could be dissolved in the filtrate without precipitating any solid. The solution has the potential to extract more of the impurities from the desired product. Besides having residual capacity to dissolve impurities, the filtrate is saturated with the desired product, which is going to be lost if the filtrate is sent as waste.

Both of these situations can very often be improved upon if a portion of the crystallization filtrate from a first batch can be used as part of the crystallization solvent in a subsequent batch.

There are other situations, easily identified, where filtrate recycling is not promising. For example, when an anti-solvent has been added to cause crystallization and this anti-solvent is not easily removed. The reason is easy to understand. Adding this modified filtrate back into a second batch will not reproduce the precipitation conditions of the first batch. It is unreasonable to expect an equivalent product.

A similar unpromising situation occurs with crystallization from mixed solvents when the product is dissolve in a first solvent and then the solution achieved diluted with a second solvent before awaiting crystallization.

In general it is crystallization achieved with the assistance of cooling that is amenable to partial filtrate recycling because the original condition can be recreated simply by reheating to the original dissolution temperature.

If x is the fraction of mother liquors you contemplate recycling in place of an equal volume of solvent and 0 < x < 1, the paper referenced above shows that the impurities in the mother liquors of each subsequent batch will tend towards a limit that at infinite batches becomes

I_infinite = I₁ X 1/(1- x)

Thus with x=0.5 and the level of impurity in the first batch I₁ = 2%

I_infinite = 2% X 1/(1-0.5) = 4%

Or with x=0.7 and the level of impurity in the first batch I₁ = 3%

I_infinite = 3% X 1/(1-0.7) = 10%

Or with x=0.6 and the level of impurity in the first batch I₁ = 0.8%

I_infinite = 0.8% X 1/(1-0.6) = 0.2%

Of course if you recycle all the mother liquors no matter what the level of I₁ is I_infinite = number X 1/(1-1.0) = infinite; that is to say the impurities come out on the product.

The motivation for recycling some of the mother liquors is not of course usually to save solvent but to increase the recovered yield of the desired product. To illustrate this, for simplicity let us suppose that what Kilomentor defines as the 'reaction yield’ (the assay of the desired product in the isolation solution as a % of the theoretical quantity of desired product) is 100%. The ‘recovery yield’ (the weight % recovered product as a percentage of the weight of desired product based on the assay yield) in this situation becomes equal to what we all call the reaction yield (the weight of product isolated over the theoretical weight of product possible as a percentage). If under these circumstances the reaction yield is 70%, there will bes 30% of the material left in the saturated mother liquors (so long as no degradation has occurred). If half of it is recycled, the overall yield will be increased by ½ X 30% = 15% and will become 85%.

Now even if the solubility product limit of all the different impurities in the mother liquor is never exceeded, the desired product which is isolated by crystallization using some mother liquor recycling will be less pure than when the technique is not used. One reason for this is that the mother liquors do contain a higher concentration of impurities and more of these by-products will either co-precipitate or be adsorbed on the pure solid crystalline product. Another possibility is that separation of the desired crystalline solid from mother liquor solution is incomplete. Mother liquor solution is trapped on the surface of the solid and evaporates there or is deposited there when the crystals are place in the drier. Certainly the wash solution used on the filtered crystal product becomes more critical both to preserve the yield improvement achieved (by not dissolving the product) and by removing this film of mother liquor without precipitating impurities.

The crystallization from a solution in which a portion of mother liquors is being recycled will likely be different from an isolation without recycling. Optimal crystallization temperature, and cooling time will change as the percentage of impurities changes. Typically crystallization proceeds more slowly in the presence of a higher concentration of impurities and greater care needs to be taken to prevent co-precipitation.

It would be unusual to recycle more than 50% of the mother liquors from one run of a campaign to the next. Remember to save all the mother liquors from run A until the product of run B certified to be trouble free. If run B has a problem and needs to be investigated, you will not want to use run B mother liquors in run C. You still want to have at least 50% of the mother liquors from run A to use while you check to see if there is some deviation in run B.

If you intend to use mother liquor recycling in a validated process, you will need to use mother liquor recycling in the validation batches and have in place the analytical testing protocols required to show that the mother liquors you are transferring from one batch to the next meet preset standards, have been stored for a validated time under validated conditions.

The Problem of Resolving Enantiomers of Chiral Basic Compounds does not have a general solution. There is no chiral acidic substance that that quite dependably will form diastereomeric salts that can be separated at useful synthetic scale .

There will probably never be a reagent that will work for resolving every enantiomeric pair but a solution might be closer than is commonly apparent. TABA which is (2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid has been available by an Organic synthesis preparation since 1973. The compound was developed initially to resolve chiral polycyclic aromatic molecules with neither acidic nor basic functional groups. It works by forming diastereomeric charge transfer complexes between the pi donor rings of the chiral polycyclic aromatic racemate and the pi acceptor, electron deficient rings of the TABA reagent.

Subsequently, the enantiomeric TAPA reagents were used to resolve chiral antimalarial agents that had large hydrophobic amine groups that formed salts poorly. [F. Ivy Carroll, Bertold Berrang and C.P. Linn. Resolution of Antimalarial Agents via Complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid. J. Med. Chem.. 1978, 21(4) 326-330.]

When the structure of the enantiomers to be resolved has both a primary, secondary or tertiary amine and a potential electron donating ring there are two points of attachment between the enantiomers and the chiral resolving agent increasing the potential for success. In the paper referenced above 5 different compounds were successfully resolved using this pair of (+)-TAPA and (-)-TAPA. No compounds are reported to have failed resolution.

Even when there is no polycyclic aromatic pi donor in the racemic basic material that you are trying to resolve a solution may be possible if the amine is primary or secondary. Introduction of a benzylic protecting group that incorporates such a pi donor might provide a new compound that can be easily resolved. Removal of the benzylic group by hydrogenolysis for example would return the resolved material that is sought.

Phenols may be separable from neutral substances by liquid/liquid extraction with aq. base, if the molecular weight is not too high. This is not a guaranteed success because phenols are only weak acids and the alkali phenolate, particularly as the molecular weight increases, may simply be water insoluble. Because the free phenol in this situation is lipophilic, the phenolate in the presence of both water and an organic phase may substantially hydrolyse back to sodium hydroxide and the free phenol. the neutral phenol “happily” jumps into the organic layer. For example, if a 10 ml. solution of 0.01 mol of 2,4-dimethylphenol is reacted with one equivalent of alkali in water and is then shaken with 20 ml of ethyl ether for about 10 minutes, the amount of the phenol found in the ether is 43% and the water is strongly basic. The amount extracted depends upon the ratio of alkali to phenol, the ratio of the phases, and the particular organic solvent used. In the case of 2-isopropyl-5-methyl-phenol (thymol) the amounts extracted by different solvents under the above conditions are: ether, 88; benzene, 38; carbon tetrachloride, 25; and pet. ether 22 percent.

In the extreme case of di-ortho substituted phenols there is steric hindrance to the solvation shell that is needed around the oxygen anion, which makes the anion formation energetically disfavoured. With di-ortho phenols, even when the molecular weight is rather low- the phenol will not dissolve in aqueous sodium hydroxide. For that reason such species were called cryptophenols in the days before spectroscopic testing, because these phenols did not give the characteristic qualitative test for a phenol. Cryptophenols can be dissolved in methanolic-KOH called Claisen’s alkali. Kilomentor has an article about Claisen’s Alkali.

Phase Switching Hydrolysis

In some situations another trick can be employed to separate a weak phenol or cryptophenol from a non-phenol. Suppose for example you are trying to separate two carboxylic acid esters that differ only because one also contains a free phenol while the other contains a phenol alkyl ether. If one places the compound mixture in a two phase solution of say toluene and water, adds sodium hydroxide to the water and stirs the phases gently after some time the phenolic ester will be found transferred to the aqueous base phase and converted to the carboxylate while the ether-ester is untouched in the toluene phase.

I have used this trick several times. It works if the phenol functionality increases the solubility of its ester substrate to a slightly greater extent in the water than the substrate containing the ethr. Once in the aqueous alkaline layer, the phenolic ester substance is quickly hydrolysed. In the form of the sodium carboxylate, it is stuck quantitatively in the water. The ether -ester on the other hand is comparatively insoluble in the water. It cannot “see” the alkali because the stirring is gentle and there is little interface so it remains unreacted in the toluene. Conditions for the separation can be optimized by adjusting the organic solvent, the stirring and the temperature of the two phase mixture.

Although I have not tried the method with any combinations other than phenol-esters and ether-esters, other functional groups might be useful to replace the phenol by creating this initial small water solubility. Perhaps thiol, primary and secondary sulfonamide, imide, terminal acetylene, alpha unsubstituted alkyl nitro or dithiane might work. Any compound that can act as a weak acid in aqueous alkali has a good chance to succeed.

I have seen a large increase in traffic to this blog after I reviewed the titles of some articles from December 2006 to March 2007. Therefore, I continue with this update.

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

I have placed at the top the blog articles that I remember had the most visits.

Wolf & Lamb Reactions or Site Isolation Reactions

10 July, 2007

Solvent Replacement: The need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process

09 April, 2007

pKas of Common Organic Substances

07 June, 2007

A Practical Scheme for Working Up a Reaction Mixture based upon real Liquid-Liquid Extraction Possibilities and Logical Solubility Testing (An updated entry)

09 June, 2007

Solvent Exchanges for Special High Boiling Solvents

29 April, 2007

Polymeric Reagents and Immobilized Catalysts: When in a Process They Can Pay the Best Dividends

08 August, 2007

Urea Complexes for the Separation of Straight Chain Solvents

29 April, 20

Purification of Chemical Products by Treatment with Mixtures of Solid Adsorbants like Charcoal: Identifying Useful Absorbants by a Combinatorial Method

14 April, 20

Alcohols: Organic Chemistry Isolations with Reversible Derivatives particularly Phthalate Esters

01 April, 2007

Improved Extractive Separations with Organic/Organic Biphasic Solvent Systems: Catalyzed Total Silylation to Improve Partition Coefficients

14 May, 2007

Imminium Perchlorates & Fluoborates: Solid Crystalline Reversible Derivatives of Carbonyls

06 May, 2007

Hydrotropes as Solvents for Extraction and Separation

22 July, 2007

Search engines have the shortcoming that they give higher rankings to recent material. This is appropriate for news, fashion and opinion but not nearly as appropriate for scientific educational materials. Thus with the passage of time it becomes harder to locate pertinent kilomentor blogs. To counteract this I am providing a review of the titles of some of the early Kilomentor articles. Regular readers can of course find all my articles in the Kilomentor archives in the kilomentor blog.

I have placed at the top the blog articles that I remember had the most visits.

Kilomentors Selected Oxidation Bibliography

08 February, 2007

Comparison of Preparative Chromatography Methods

30 December, 2006

Balancing Chemical Equations and Calculating Heats of Reaction: Two Often Overlooked

Helps for Chemical Process Developers.

28 February, 200

List for Developing a Scaled up Step in a Chemical Process

30 December, 2006

What to Do When Your Chemical Reaction Fails?

02 February, 2007

Context of Process Chemical Development Training

04 January, 2007

Separation as the Focus of Process Development

19 January, 2007

CheckDerivatives that make phase switching easy-The Preparation and Use of Alcohol Sulfuric Acid Esters

24 January, 2007

The Carboxylic Acid Group- A functional group that make phase switching easy

24 January, 2007

Simple, Rapid Optimization of a Chemical Process Step

24 February, 2007

Inorganic Non-Stoichiometric Metal Salt Complexes with Organic Molecules as a particularly Useful Method for Purifying Neutral Substances.

16 February, 2007

Dissociation Extraction and Dissociation Leaching and so called Dissociation Extraction Crystallization

11 February, 2007

Stoichiometry & the Rate of Addition of Reactants: An Important Consideration for Mentoring / Training in Chemical Process Development

09 March, 2007