A significant factor in solvent choice for a process step is the problem separating the product from the solvent both grossly (as in filtering a solid away from a crysatallizing solvent, and more completely as in drying of solid moist with solvent. In the gross separation high boiling solvents tend to be more viscous than lower boiling solvents and filtration is slowed by increasing viscosity. In the drying step higher molecular weight solvents are generally harder to remove by evaporation.

In a recent block pertaining to solvent replacement, ”Solvent Replacement: the need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process” April 9^th 2007, Kilomentor suggested the possibility of using a high boiling n-paraffin, or dibutyl ether, or a polyethylene glycol as a chaser and then removing that solvent as a urea inclusion complex.

I proposed this, not as an established or even exemplified procedure, but only as something that could be expected to work. A paper has just appeared, commenting again on the need and the difficulty of removing high boiling dipolar aprotic solvent residuals when isolating pure reaction products. [Removal of Reaction Solvent by Extractive Work-up: Survey f Water and Solvent Co-extraction in Various Systems, Laurent Delhaye, Attilo Ceccato, Pierre Jacobs, Cindy Kottgen, and Alain Merschaert. Organic Process Research & Development, 2007, 11, 160-164.] This article was published on the web. [ http://pubs.acs.org/cgi-bin/abstract.cgi/oprdfk/2007/11/i01/abs/op060154k.html. ]

Perhaps one solution will be found by using dipolar aprotic solvents that are effectively linear and longer than eight atoms, because it is these molecules which can be cleaned out of the final product using urea complexes.

I would like to offer some further literature support for this idea now.

Urea complexes of polyethylene glycol, dibutyl ether, octadecane and diethylene glycol are known in the literature and are made in the established way.

Also, the literature already provides experimental details for making urea complexes of the n-paraffins from light gas-oil and heavy gas-oil petroleum fractions. [Ind.Eng. Chem. Res. 1997,36, 3110-3115, Separation and Characterization of Paraffins and Naphthalenes from FCC Feedstocks. A.A. Lappas, D. Patiaka, D. Ikonomou and I.A. Vasalos].

The paper teaches the separation of the n-paraffin fraction from fluid catalytic cracking using urea. This teaching encourages one to understand that n-paraffins even when present as a substantial portion of a mixture, as it would be if it were the residual solvent after a concentration, can be separated . Sufficient urea is added along with a polar compound (activator ) such as water, aliphatic alcohol, or ketone, which expedites the completion of formation. In fact methanol is usually used as this catalyst.

The procedure provided in the paper is quoted:

“Separation of n-Paraffins by Urea Adduct Formation. The entire separation procedure for the non-aromatic fraction is described in Figure 1. The typical removal procedure of the straight chain hydrocarbons (n-paraffins) from heavy or light gas-oil is (i) 15 g of urea and 5 g of HGO (or (LGO) aliphatic hydrocarbons (isolated by elution chromatography-ASTM D-2549) are placed in a 250 ml flask and stirred for 0.5 h at 55-60 C by6 adding 25 ml of methanol and (ii) the miture is stirred for 1.5 h in room temperature and for 0.5 h at 10 C. The solid adduct is washed with hexane (60 ml) and filtered off”.

The commentary on this procedure in the paper was:

“….The key factor which affects the entire procedure is the effective contact between urea (or thiourea) and the paraffinic substances. This contact is influenced by the amount of excess urea and methanol. The following excesses are necessary for satisfactory separation;25 ml of methanol and 15 g of urea for paraffin separation …….The stirring of mixtures at some very specific temperatures is also very important. The initial heating must be at 55 C for a period of 30 minutes. This serves to increase the rate of adduction of the heavier n-paraffins through increased solubility and diffusion in the methanol-urea phase. By decreasing the final adduction temperature to 10 C, the recovery of compounds such as C13 and above is improved…..”

It would seem that this advice can be useful devising conditions to remove uniform molecular weight, high boiling, straight chain solvents. In fact, this should be a simpler case. A single optimal temperature for adduct formation tailored to the particular solvent and another temperature to maximize yield for filtration could be expected to work well. What only experimentation can discover is to what extent solutes are selectively excluded from the urea complexes, in any particular reaction mixture. Besides the straight chain high boiling solvents already mentioned we can imagine diglyme, triglyme and tetraglyme behaving effectively the same way.

The following articles show examples of these molecules forming complexes.

Redlich, O.; Gable, C.M.; Dunlop, A.K. and Miller, R.W.. Addition Compounds of Urea and Organic Substances. J. Am. Chem. Soc. (1950), 72, (4) 153-60 .

Topchiev, A.V.; Roozenberg, L.M.; Nechitailo, N.A.; and Terent’eva, E.M., Khurnal Neorganischeskoi Khimii (1956), 1, 1185-93. (Russian)

C.A. 49, 11559b.

Geiseler, Gerhard; Richter, Peter. Urea-adduct formation of position-isomeric n-alkane derivatives. Chemische Berichte, (1960), 93, 2511-21.

Hild, Gerard. Macromolecular addition compounds. I. Research on urea (or thiourea) addition compounds with poly (oxyethylenes). Bulletin de la Societe Chimique de France (1969), (8), 2840-54.

Treatment of a solution of a chemical product is a trivial matter if you are working in an Erlenmeyer in the laboratory, but much more problematic for a chemical process engineer at-scale in the plant. Charcoaling as a means of removing small (<2%) amounts of contaminating substances from an organic preparation has long been known. Use of a plug of a solid adsorbant (such as silica or alumina) through which a solution of the slightly impure substance is passed for the purpose of purification is also long known.

There are other similar techniques. The use of these methods has been empirical and a matter of one at a time testing trial and error. In particular the selection of a solvent to be used in combination with these solid adsorbants was empirical and this was a very real problem because it is often the combination of the correct choice of solvent and the correct choice of solid adsorbant, which produces the acceptable desired purification.

I now propose the use of statistical methods and /or combinatorial chemistry to solve the problem. Thus although the problem has been long in existence, such a method has not been described and is not part of the common knowledge of those skilled in the art of purification.

The basis for the method---taking several reagents and mixing together—is normally very limited because as often as the reagents will react with the substrate, they will react with each other. It has long been known however that polymeric reagent do not have this problem. This has been shown most clearly with organic functionalized polymers (used in Wolf/lamb reactions) but it can be inferred to be equally true with inorganic polymers such as carbon, silica, fluorisil and alumina) for example. As a consequence the effects of polymers on the removal of impurities from a dissolved sample should be purely additive. The dissolved substrate will move around between the two insoluble adsorbants with each adsorbant removing what it has attraction for from the solution. Since the one polymers cannot one invade the pores of the other, they cannot interact with each other.

This being so, it should be possible to perform a trial separation to purify an organic chemical dissolved in a solvent by mixing the sample with a mechanical mixture of adsorbents such as( Norit A, Sarco KB, Celite, silica gel, alumina, reverse phase silica, clay, strong acid ion exchange resin, strong base ion exchange resin, macroreticular resin, florisil, EDTA salts, unfunctionalized DEG cellulose, calcium chloride, manganese chloride, lithium bromide or calcium bromide to name a few. Obviously certain simpler combinations would be better to test. If upon filtration of the sample and reanalysis of the residue the offending impurity has been removed or substantial reduced in a relative sense the job is simply to deconvolute to discover the element or simple combination of adsorbant elements that has the effective action. If there is no appreciable effect, there is a good likelihood that none of the members of the combination are excellent at the impurity removal. Another combination of candidate adsorbants and another condition of solvent, temperature and time is tried until a useful positive result is identified.

It should be realized that macroscopic properties of the solvent medium such as pH will have their own interactions with each of the adsorbents.

For many years my research teams have combined Norit A and Darco KB for the purpose of checking on the ability of these carbons to decolorize slightly impure products. This is my only experimental evidence that this methodology will work. Just theoretically it makes sense.

The need for solvent exchanges

The need for solvent exchanges in the sense of displacing one solvent by another without passing through a liquid free state practically does not exist outside of process chemistry. At laboratory scale, when one solvent needs to be replaced with another, the solution contents are placed in a r.b. flask, set spinning on the vacuum rotary evaporator with appropriate heating and strong condensing efficiency. When the first solvent has been completely evaporated then the required new solvent is added and the solutes brought back into solution by swirling and scrapping.

On scale, evaporation to dryness is not possible without caking and possibly charring. Even if it were possible to avoid degradation, the layer of non-volatile residue would become so thick on the reactor's wall that heat transfer to complete the evaporation would be made impractically. Combined with this difficulty, at low volumes in a normal reactor stirring becomes ineffective. Thus solvent replacements must be done without completely removing the liquid phase at any point.

As an exercise let us consider solvent replacements among a dozen of the most common solvents. This examination is a logical analysis. None of the more complex multistage switches have been experimentally verified. The only inputs are known miscibilities, boiling points and the data from binary azeotrope tables.

The solvents are listed with their boiling points. I have named the list, Common Reaction Solvents, because they are not all solvents of choice for process chemistry. Chloroform for example would not be used today in a chemical process and hexane because of its flash point is questionable.

12 Common Industrial Solvents

Methylene chloride 39.6

Acetone 56

Chloroform 61.2

Methanol 64.5

Tetrahydrofuran 66.0

Hexane 68.7

Ethyl acetate 77.1

Ethanol 78.3

Isopropanol 82.2

Toluene 110.6

Dimethylformamide 153.0

Dimethylsulfoxide 189.0

Modern synthetic chemistry has most recently been influenced by the retro-synthetic analytical procedures of E.J. Corey. This analytical method has provided a quantum leap in the productivity of synthetic chemistry. Taking this a step further, exactly because organic synthesis is a creative activity examining any synthesis target will benefit from a variety of inspiring perspectives. The retro-synthetic route is product focused. By this I mean that the analysis is inspired by the connectivity and the relative functional group orientations of the target molecule. How could it be any other way one might ask? The target connectivity is the objective, which must be reached and it cannot be ignored and that is correct. What I am saying is that the Corey retrosynthetic analysis looks for inspiration and direction essentially single-mindedly at the connectivity and positional relatedness of the functional groups.

Are there other ways? Yes. In fact historically, preceding the Corey-Wipke retrosynthetic methodology the approach was to look in the product for the substructure of a closely related but commercially available starting material and then attempt to interconnect starting material and product by some combination of skeletal bond forming reactions and functional group manipulations.

Molecules related to steroids are still analyzed in this way both for historical reasons and because our minds intuitively grasp the logic of the method. Who would look at an unusual structural feature or functional group arrangement in a steroid and then think that an entirely different preparation of the tetracyclic steroidal skeleton would be the preferred approach?

There are other subliminal assumptions shared by both the Corey-Wipke method and the starting material focused approach. They are the assumptions that efficiency and elegance in synthesis relate to minimizing the number of chemical reaction steps and the assumption that the physical properties of the intermediate are irrelevant to the simplicity and elegance of the synthesis.

We have already understood that molecules, which are effectively basic or effectively acid in aqueous solution have special ease of isolation and purification because of their ability to form salts and to be partitioned between organic media and aqueous pH adjusted media. That is, they can be formed into a large number of solid ionic salts which can be recrystallized for purification and can then be neutralized to return the origin neutral substance.

Not quite so convenient will be functional types which can reversibly form derivatives that are acids and bases, which can be purified by the above-named means and which can then be reconverted back into the original functional groups. Such manipulations of course suffer from the increased number of steps. Let us take the example of an alcohol, which is converted into a potassium O-sulfate salt, is recrystallized, and then is hydrolyzed back to the alcohol. Three additional steps have been introduced and one is no further along in terms of synthetic transformations.

One thing that this is telling us is that there is inadequate knowledge about the transformations of potassium alcohol sulfates. If it were possible to change the synthetic path so that the potassium O-sulfate salt was not just a substance that allowed easier purification but which also was an intermediate important in the process of bond building and/or functional group transformation, then the sequence would go alcohol to potassium alcohol sulfate (with attendant purification) followed by potassium alcohol sulfate to another more advanced intermediate in the synthetic route.

If we follow the strand of reasoning that has led us to reversibly forminge polar or ionic derivatives, we will find that there are other reactions of neutral functional groups which lead to purification but without the step of recrystallization of the derivative. These are the organic-inorganic complexes most frequently those with lithium chloride, bromide and iodide; with magnesium chloride and bromide; with calcium chloride and most frequently bromide. These complexes are useful because most organic process intermediates are hydrophobic and are soluble in hydrocarbon ether and ketone solvents and can complex as preferred bases in these solvents with the above Lewis acids. These complexes are insoluble in these solvents. They may be stoichiometric but usually are not and the Lewis acid selects the neutral function group with which to preferentially complex based on the steric environment in the substructural region around the functional group which is acting as the Lewis base. The lack of stoichiometric relationship in these complexes is practically not important because:

• it is easy to separate hydrophobic organic compounds from inorganic salts
• the inorganic Lewis acids are relatively inexpensive and readily available

Among common organic functional groups alcohols and phenols are the most amenable to forming complexes with Lewis acids. Alcohols form complexes with calcium chloride, calcium bromide, and lithium salts and phenols form complexes with calcium bromide in particular. Kilomentor has already written a blog specifically about such complexes: Inorganic Non-Stoichiometric Metal Salt Complexes with Organic Molecules as a particularly Useful Method for Purifying Neutral Substances.

Alcohol Reversible Derivatization for Acid-Base Extraction

Here I would like to focus on the use of actual covalent derivatives of alcohols, which convert them into acid substances. in particular I would like to talk about alcohol phthalates.

Alcohol Phthalates

Phthalic anhydride is an inexpensive alcohol derivatizing agent, which produces a product which is a carboxylic acid containing a hydrolysable ester functionality. The presence of the carboxylic acid allows salt formation and that provides some water or water-alcohol solubility, which can be used for extractive separations from by-product contaminants.

Sodium salts of straight chain alcohols larger than octyl tend to form emulsions so the process for their preparation needs to be chosen with this possibility in mind. The alcohol is heated with twice the molar amount of phthalic anhydride at 105-110 C for a period between thirty minutes to two hours. The higher the molecular weight of the alcohol the longer the reaction typically takes. The m.p. of phthalic anhydride is 131 C.

The reaction mass is treated with ether, 50 ml/gm of starting alcohol and the excess phthalic anhydride which is insoluble in ether is filtered off. The ether solvent is then removed and the residue is treated with about 120 ml of water and the bi or tri-phasic mixture is warmed at 60-65 C for 45 minutes to hydrolyze any residual phthalic anhydride. Then the water is also stripped off or if the residue is solid it can be filtered and the residue dried. The dried residue is dissolved in 20 cc of chloroform in which phthalic acid is insoluble and the solution filtered. Again the solution is evaporated under vacuum and the esters recrystallized three times from petroleum ether. It is often found advantageous to use dry-ice for cooling the solutions of the esters and using an inverted siphon filtration. This procedure is for a laboratory sample as one can easily see.

When the shape of the molecule makes emulsion formation less likely a simpler procedure can be used. One gram of the alcohol is heated as before with twice the stoichiometric amount of phthalic anhydride for 30 minutes to two hours at 105-110 C as before. If the alcohol is not liquid some toluene is used to create liquidity and prevent charring in the flask. For purification the mixture is shaken with 50 ml of toluene diluted if necessary with hexanes filtered from excess anhydride and the filtrate neutralized by dilute sodium carbonate leaving the mixture slightly acidic. The aqueous layer was extracted three times with 100 ml portions of toluene too remove the unreacted alcohol and possible diesters (the extraction solvent must take the starting material solubility in mind). Some alcohol way be needed in the aqueous phase to hold some high molecular weight or multifunctional alcohol mono-phthalates in the polar medium. The esters are then precipitated from the aqueous solution by dilute hydrochloric acid and recrystallized from an appropriate solvent mixture. Often a mixture of predominantly petroleum ether mixed with around 10% of toluene will work well (hydrocarbons). [James F. Goggans, Jr. and J.E. Copenhaver, J. Am. Chem.. Soc. 61, 2909 (1939).]Procedures for making the monophthalate esters of secondary alcohols have been described by Pickard and Kenyon, J. Chem. Soc., 91, 2058-2061 (1907); 99, 58 (1911): 103, 1937 (1913).

For preparing monophthalates of tertiary alcohols a good procedure involves the treatment with ethereal triphenylmethyl sodium at room temperature. The alcohol is dissolve in a convenient amount (30 parts) of anhydrous ether was added rapidly with stirring an ethereal solution of triphenyl methyl sodium until a persistent red coloration was present in the solution. This shows a residual slight excess of the colored base. Phthalic anhydride was added all at once in an equamolar amount with the alcohol and the stirring was continued for 1-2 hours. Water (200 ml) was added for each 5 gm of starting alcohol, the layers separated, and the water layer was poured over cracked ice and hydrochloric acid. The acidic cold medium neutralizes and precipitaes the free acid. the precipitate formed was filtered cold, air-dried, and recrystallized or triturated. In the old literature the derivative is repeatedly recrystallized.

Kenneth G. Rutherford, Joseph M. Prokipcak, and David P.C. Fung, J. Am. Chem. Soc., 28, 582, (1963).

It is not clear at what point the yield was lost. Smaller alcohols gave lower yields. The average yield for several derivatizations of t-butanol was 65%. It would not be surprising if the preponderance of the yield loss was in the recrystallization step. If the sequence is used to purify the material from non-alcohol non-reacting substances, then the crude can be immediatedly hydrolyzed and the alcohol taken back into an organic solvent and recovered from there or used as such in the next reaction. The phase shifts will have done their job of removing impurities and the derivative will have served as a stopping point in the process. In a process we must recall, an appropriate intermediate purity needs only to be the practical purity which is required to give a final product meeting the specifications. The ruggedness of the process is not so much determined by the absolute purity of the recovered intermediates but by the number and the discrimination of the phase shifts that the process provides.

Another way to prepare monophthalate esters is to use amino pyridine catalysis of the acylation process. A method is provided in Synthesis Communications, 1972, 619.

Thus t-butyl hydrogen phthalate is obtained under very mild conditions using phthalic anhydride and 1.2 equivalents of 4-pyrollidinopyridine in dichloromethane at room temperature. Using triethylamine requires long heating. In the actual procedure t-butanol (1.0 gm 13.5 mmoles) was added to a solution of phthalic anhydride (1.48 g., 10 mmol) and 4-pyrollidinopyridine( 1.8 g, 12.5 mmol) in dichloromethane (10 ml). The NMR spectrum indicated 95% conversion of the anhydride after 1 day. after 2 days, ether was added and the base extracted with 2N hydrochloric acid. The ether layer was dried (MgSO4) and evaporated in vacuo. To remove phthalic acid, the oily residue was dissolved in carbon tetrachloride (10 ml) and the solution filtered. The filtrate was evaporated and the remaining oil dried at 50 C/0.05 torr.; yield 2.15 gm (97%) mp. 70-75 C.

This yield is based on phthalic anhydride, which was the limiting starting material. We would be using the reaction to perform a phase separation to remove alcohols from non-alcohol constituents and the phthalic anhydride would be used in an excess. The reaction mixture would contain neutral, non-alcohol, base soluble alcohol monophthalate and the acid soluble dialkylaminopyridine catalyst.

In the reference it says. In preparations on a larger scale (>2 g) in addition to catalytic amounts of 4-dialkylamino pyridine one equivalent of triethylamine was used to bind the acid formed in the reaction. In this case longer reaction times or heating was necessary. as a reaction medium there may be used a non-protic solvent, excess triethylamine or excess anhydride.An example of a s-alcohol is given in which the phthalic anhydride is used in excess

(-) Menthyl Hydrogen Phthalate

A solution of (-) menthol (3.2 g, 20 mmol) phthalic anhydride (6.0 g. 34 mmol), triethylamine (4.1 ml, 30 mmol), aand 4-dimethylaminopyridine (0.5 g, 4.1 mmol) in dioxane (20 ml) was kept at room temperature for 6 hours. Work-up was done as for making the t-butyl phthalate by adding an excess of ether and extracting with 2N hydrochloric acid to remove the catalyst and the triethylamine hydrochloride and the dioxane solvent. the ether solution was dried with magnesium sulfate and after filtering evaporated to an oil which was redissolved in carbon tetrachloride on any suitable solvent which dissolves the product but leaves the phthalic acid insoluble. carbon tetrachloride is appropriate. Filtering the insoluble phthalic acid leaves a solution of the monophthalate in carbon tetrachloride. The yield was 5.6 g (92%) m.p. 90-93 C; after one recrystallization from methanol/water m.p. 111 C. Phthalic acid and the menthol monophthalate are likely to be even more simply separable. By extractive crystallization if the aqueous solution in contact with an organic solvent is partially neutralized with base. The sodium salt of phthalic acid will selectively partition into the water and the menthol monophthalate will be retained in the organic phase. Thereafter the derivative can be immediately hydrolyzed with base, acidified and the menthol extracted into an organic phase.

Another application of the same technology is the removal of a small amount of an alcohol, mono, sec or tertiary from a main product, which is not an alcohol and is unreactive with phthalic anhydride.

An example might be the removal of residual alcohol from the pinocol rearrangement products from a diol. The product ketone will be unreactive to the phthalic anhydride, catalyst and base. When the impurity has been derivatized at either one or both of the alcohol functions; then one extraction to remove the catalyst and base, followed by an alkaline extraction to remove the monophthalate will leave the neutral ketone alone in the organic solvent. The ketone product may at this stage be of sufficient practical purity to be used in the subsequent reactions without by-products, which reduce the final product quality analysis.

In another example the mixture of primary and secondary alcohols formed in the Fischer Tropsch synthesis was first separated into primary alcohols and secondary alcohols by preferential separation of the primary alcohols with phthalic anhydride. [Graves, Ind. Eng. Chem. 23, 1381 (1931).

Besides using phthalic anhydride other anhydrides can be used in the same way. In an example from the recent patent literature (WO2005084643A1) the drug substance escitalopram (not an alcohol) is purified to remove an alcohol impurity by reaction with succinic anhydride. The alcohol alone reacts and the hemi-succinic acid derivative is extracted into an aqueous phase with an ammonia solution leaving the purified escitalopram in the organic solvent.

Pros and Cons

You may say that a lot of labor and reactor time has been spent removing a by-product when crystallization of the crude mixture would have produced the same result. The payback comes when one looks at the recovery yield from the crystallization of a product which ahs been purified by derivative formation and phase shifting.

To make this point let me ask you a general question. If one has a product mixture which is 90% desired product and 10% by-product or co-product and one recrystallizes; what yield can you realistically expect as a median result? Remember that when 8/9ths of the product has crystallized the remaining mixture will be 50:50 product and by-product. Even with the by-product being entirely retained in solution, it is most likely that the last 10% either will not crystallize or will crystallize so slowly that it will not be economical to wait for it. Thus the median yield will be 80%. Non-suppose that by phase shifting of a derivative the purity before crystallization is 99% product 1% coproduct.

Now when one recrystallizes the 50:50 mother liquor situation only occurs after 98% of the desired product has crystallized. The potential yield will be 98% in a short time. Much less solvent will be used and simple slurrying rather than crystallization make be satisfactory to get practical purity. Now suppose one lost 10% of the material during the operations of the phase shifting derivatization and this is a very generous assumption of loss. Still one would have 88% product compared to 80% a saving of 8% of the material. An advanced intermediate moreover is costly because a lot of materials and labor has been invested in it. Spending some phthalic anhydride, DMAP, triethylamine and solvent and inorganic acids and bases can be a very good investment.

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