Tannic Acid as a Promising Hydrotrope For Separation and Purification of High-Value Products

Most hydrotropes are made by dissolving organic salts at a concentration of at least 1M in water. Covalently bonded materials do exist that form hydrotropes. The best known is urea. Another inexpensive, non-ionic organic material that is highly soluble in water and that can be expected to promote the dissolution of other organic substances is tannic acid.     
                 
Molecular Formula - C₇₆H₅₂O₄₆
Molecular Weight - 1700
Melting point - 218°C
Water solubility - 1g/ 0.35 ml

Speaking roughly to produce a hydrotrope a chemical must dissolve in water to give a 1M solution. A 1M solution of tannic acid would contain 1700g of organic solid per liter of water. That would be 1.7 gm per milliliter. The solubility of tannic acid in water is 4.88 gm per milliliter. One could achieve a solubility of 2.87M if required in a saturated solution. Tannic acid is a material available in industrial quantities at a practical price. Sigma-Aldrich sells 500 grams for less than $100.00. Considering that only 60 g of urea are needed to produce a 1M aqueous solution that would give an effective hydrotrope and supposing that we provide three times as much tannic acid by weight, that would just be 180 g per liter that would not cost more than $75.00!

The molecule shown in the figure is only one representative (perhaps the major one) of the constituents of the organic mixture called ‘tannic acid’ but if we recognize that it is typical then each molecule can be approximated to contain 25 phenolic groups and 10 ester linkages. The phenolic groups alone would comprise over 15 hydrogen bond acceptors and 25 hydrogen bond donors.

 Opportunity for Undergraduate Chemistry Major Project

Could a hydrotrope of tannic acid selectively extract organic compounds dissolved in organic solvents typically used in industrial process chemistry? Could it simply solve otherwise difficult separation problems in the fine chemicals or pharmaceutical products industries? These are important questions that could be answered by the research for an undergraduate organic chemistry major's project.

The Use of Methyl or Ethyl Salicylate to Crystallize Solutes Insoluble in both Hydrocarbon Liquids and Water

The following is a research idea. As far as KiloMentor is aware It has not been demonstrated. Before any new research experiments are started an up-to-date literature search is recommended.

A very large number of organic compounds are essentially insoluble in both pure hydrocarbon solvents and in water. As such they would be expected to also be insoluble in a two-phase mixture of water and hydrocarbon. Solutes that belong to this large group would be candidates for a crystallization/recrystallization procedure that, as far as I know, has not been tried to date.

Methyl and ethyl salicylates are very low melting solids and high boiling liquids: methyl salicylate mp -8.6 C; Bp 220-224 C; ethyl salicylate mp 1 C; Bp 232.5 C.

They share another common property. When stirred with aqueous alkali they are hydrolyzed to 2-hydroxybenzoate salts. What is less commonly recognized is that the presence of a separate hydrocarbon phase would not effectively inhibit this hydrolysis. The reason: the free phenolic substituent essentially drags the ester into the aqueous phase where the base attacks the ester functionality irreversibly after which it no longer has any affinity for the hydrocarbon layer. 

Unlike hydrocarbons or water, these compounds will be good solvents for a wide variety of other organic materials. They can interact using Van der Waal dispersion forces, dipole-dipole interactions, and hydrogen bonding using both the phenolic hydrogen bond donor and the ester carbonyl hydrogen bond acceptor. Furthermore, these compounds are not particularly expensive and are readily available at industrial scale. They have been demonstrated to be safe. Methyl and ethyl salicylates are flavouring and perfume chemicals. 

 
Suppose we choose to dissolve a solute of interest in a combination of a highly apolar poor solvent, like the hydrocarbon heptane for example, and as solubilizing agent methyl or ethyl salicylate. Such a combination will have the property of having a boiling point at least as high as the hydrocarbon used but will have the enhanced dissolving power provided by the additive. When the mixture is all a single solution it is cooled to ambient temperature and an immiscible aqueous solution of base is added. Even with only very weak stirring hydrolysis in the two-phase medium will result in the salicylate being taken into the aqueous phase. Now with its solubilized degraded neither hydrocarbon nor aqueous phases will have appreciable solubility for the substrate so it should slowly crystallize out.

Wide Range of Acceptable Solutes

Even solutes containing functional groups sensitive to aqueous alkali can be expected to safely undergo this treatment. Molecules without active hydrogens (such as phenols, carboxylic acids) will not be extracted out of the hydrocarbon phase and so will be protected from significant alkaline hydrolysis.

Hypothetical Examples

An example of a preparation that might be improved using this methodology can be found in Organic Synthesis Col. Vol. 1 pg. 60 Anthrone Synthesis. The anthrone is finally crystallized from 3:1 benzene and petroleum ether. It is reported that about 12 g of the 3:1 mixture is required for each gram of anthrone.  The yield percent recovery is 62/82.5. An effort is made in this preparation to recycle mother liquors and this reuses about 2/3 of the liquid. The anthrone is much more soluble in benzene than in the petroleum ether antisolvent.  It would be interesting to see how the purification would proceed with heptanes as antisolvent and one of these hydroxyl benzoate esters as the solvent with dissolution at the reflux temperature of heptanes.

Another opportunity to use this technology seems to be presented by the bromination of anthracene to 9, 10-dibromoanthracene. A process is described in Organic Synthesis Col. Vol. 1 pg. 207. This procedure uses carbon tetrachloride as solvent. This would be unacceptable in scale-up today since carbon tetrachloride is a recognized carcinogen.  It might work to brominates anthracene with bromine in heptanes. The dibrominated product is likely to be poorly soluble in heptanes and anthracene itself would only be somewhat better. In the heated reaction mixture, the anthracene would probably dissolve enough to allow the reaction to proceed. At the end the crude dibromoanthracene would be precipitating. To recrystallize and recover the solvent one of our salicylates could be added with heating to get solution; the combination then filtered hot; dilute aqueous alkaline to hydrolyze and extract the hydroxyl benzoate ester. Since the 9, 10-dibromoanthracene would then become insoluble both in the aqueous and the hydrocarbon phases it would crystallize.

Other Possible applications

Other compounds from Organic Synthesis that could benefit from purification from a two-phase mixture of aq. alkali and high boiling hydrocarbon solvent: desoxybenzoin pg. 156: desyl chloride pg. 159; dibenzalacetone pg. 167; ethyl 2,3-dibromo-3-phenylpropionate pg. 270; m-nitroacetophenone pg. 434; Organic Synthesis Col. Vol. III acenaphthenequinone pg. 1; acenaphthenol-7 pg. 3;   

Removing Residual Triphenylphosphine Oxide from Reaction Mixtures

Triphenylphosphine oxide is a common and annoying coproduct in the Wittig reaction, for example. Many ways have been proposed for the separation of this contaminant but most are not fast, cheap, rugged, or necessarily quantitative. It would be a valuable contribution to chemical science if someone demonstrated the following treatment.

It is known that triphenylphosphine oxide forms large blockish cocrystals with N-acetylglycine with a very strong hydrogen bond between amide and phosphine oxide. It can be imagined that these adducts further associate as dimers through the free carboxyl group producing an even high molecular weight dimeric adduct. Perhaps the addition of excess N-acetyl glycine into a solution of desired product and triphenylphosphine oxide impurity could precipitate the cocrystals and perhaps residual N-acetyl glycine. This has not been established. But, if it works filtration would give a purified solution of the desired product with just some residual dissolved N-acetyl glycine and so long as the desired product is not acidic, this residual N-acetylglycine will be cleanly back-extracted into aqueous base.

Further Data Needed for a New Reagent to Separate Aldehydes Cleanly

This subject provides a tremendous opportunity for an undergraduate to get publishable work.

For 40 years I have been thinking about writing something about an article published in  Chem. Pharm. Bull. In 1980. Shunsaku Ohta and Masao Okamoto, in that year, published a three-page communication that taught a method for extracting aldehydes selectively into an aqueous layer and then simply recovering them in pure form and high yield. I expected to find more complete details later along with experimentation to support a hypothesis for the mechanism of action and subsequently many applications of the method. Nothing could be further from reality. There does not seem to have been any further work or use!

What the authors taught in Chem. Pharm. Bull. 28(6) 1917-1919 (1980) was that 1.2 M 6-aminohexanoic acid sodium salt solution could quantitatively convey aldehydes from mixtures comprising at least one aldehyde in either diethyl ether or diisopropyl ether into an aqueous phase and, after separating the water and organic solvent layers, the aldehyde could be liberated by acidifying the aqueous phase to pH 4-6 and back extraction into an organic phase….. free of non-aldehydes (including ketones). If emulsions formed during the initial extraction the addition of a little isopropanol was taught to break the emulsions.

6-aminocaproic acid (6-aminohexanoic acid) is cheap since it is the monomer for making nylon! So this procedure seems very practical.

Of course, it may not work! Perhaps that is why nothing more has been written about it. But surely it is worth investigating.

The authors pictured this isolation as proceeding through the formation of the imine the covalent bond of which pulled the aldehydic moiety into water courtesy of the sodium carboxylate functionality on the other end of the reagent. The authors do not offer any explanation however of why the equilibrium so greatly favors the imine. 

How high can the molecular weight the aldehyde be and still have it successfully transferred to the aqueous phase? What organic solvents can be used besides diethyl ether or diisopropyl ether? All remain clouded.

New Antisolvents for Swish Purification

Swish purification and concentrates of impurities made using swish TLC could usefully be studied using constant boiling azeotropic mixtures which are predominantly either water or hydrocarbons but contain small amounts of other solvents which could provide a useful boost to the overall solvency. Hydrotropes with an appropriately controlled amount of organic ingredients to increase organic solubility could be used in the same way for swishing. 

Examples of azeotropes that might be expected to only dissolve small amounts of many organics might be:

97.0% water; 3.0% acetic acid azeotrope bp 76.6 C

91.0% water; 9.0% Benzyl alcohol azeotrope bp 99.9ºC

95.5% hexane; 4.5% allyl alcohol azeotrope bp 65.5ºC

97% hexane 3% 1-butanol azeotrope bp 67.0ºC

94.5% carbon tetrachloride; 5.5% isobutanol bp 75.8 C

96.0% hexane; 4.0% propanol bp 65.7 C

90.0% water ;10.0% 1-octane bp 99.4 C

These constant boiling mixtures are selected because each one is either predominantly water, a hydrocarbon or carbon tetrachloride. They should be tested for their usefulness for swishing. None of these separate into two phases on standing at room temperature.

Another class of anti-solvents that might be tested for use in swishing are hydrotropes. Aqueous solutions of such compounds as 

aromatic sulfonate salts

aromatic sulfonic acids

salts of benzoic acid and substituted benzoic acid

glycols

urea

4-isopropylbenzenesulfonic acid calcium salt

2,4-dimethylbenzenesulfonic acid sodium salt 40%

p-toluenesulfonate sodium

ethylene glycol monobutyl ether O-sulfonate potassium

potassium saliscylic acid

Each made up at an appropriate concentration to only dissolve a small amount of sample.

Calcium bromide dihydrate to Precipitate Neutral Organic Intermediates in Chemical reaction Routes

In the Kilomentor blog article titled Inorganic Non-Stoichiometric Metal Salt Complexes as a Useful Method for Purifying Neutral Organic Compounds solid complexes were obtained by mixing a 15% by weight solution of calcium bromide dihydrate in amyl methyl ketone and a solution containing an organic mixture that contained steroidal ketones also in amyl methyl ketone. These solid complexes could be decomposed to yield these steroids in a highly concentrated isolate.

These are from the experimental examples of the patent, not from the claims. This is important because claims are based on extrapolations which are often overly optimistic. What these examples are promising is that any large organic molecule containing functionality, even different from alcohol (here ketone), might be precipitated as an insoluble complex from a solution in a low molecular weight ketone using a solution of calcium bromide dihydrate!

The question this begs is what range of larger neutral organic molecules can be isolated/concentrated using such reagents? Finding simple, inexpensive, rugged means to isolate neutral intermediates in chemical reaction sequences would be publication worthy, while the chemical skill to execute the experimentation would not be demanding.  

Use of Silver Nitrate Complexing to Separate Olefin Containing Compounds

An article from my blog, Kilomentor is reproduced below.I have identified in bold italics questions, that at least at the time of writing, were unanswered by experiment. 

In Organic Synthesis Coll. Vol. III a mixture of cis and trans cyclooctene is separated by mixing somewhat more than two molar equivalents of an aqueous silver nitrate solution with a pentane solution of the cis and trans compounds. The cis compound does not form any adduct and so remains in the pentane solvent. With vigorous stirring the trans compound forms a complex and dissolves in the aqueous phase. Although silver is an expensive reagent, at least in principle, it is recoverable, so it can be considered for use at scale. Winstein and Lucas studied the complexes formed between silver nitrate and unsaturated hydrocarbons and found that in some cases these are solids useful for isolation and purification.[J. Am Chem. Soc. 60, 836 (1938)]. Complexes that are solids can be recrystallized, often from hot alcohol. It is not clear whether functional groups besides double bonds interfere with separation in this way, although only hydrocarbons have been described in the literature. It is not apparent why a number other functional groups would be incompatible with the method. It may just be that, when other functionalities are present, there are better known options for separations. 

The Diels-Alders adduct between norbornadiene and cyclopentadiene contains two double bonds and forms a 2:3 hydrocarbon/silver nitrate adduct [Am. Soc. 81, 4273 (1959)]. The Diels-Alder adduct between norbornene and cyclopentadiene contains only one olefin group and was purified using its 1:1 adduct [Am. Soc. 86, 2188 (1964).].From work with the mixtures of 1,3; 1,4; and 1,5- cyclooctadiene, it has been shown that silver nitrate forms complexes with each of these, but they have different stabilities, and can be separated by using different temperatures. The weak complexes are only isolable at low temperatures [J. Chem. Soc. 312 (1954)]. The natural triene humulene was purified as a silver nitrate complex containing 2 molar equivalents of silver nitrate [Australian J. Chem. 14,272 (1961)][Tet. Let. 1977 (1965)].

It is interesting to speculate whether an aqueous solution of silver nitrate could be used to remove the olefin from a mixture of olefin and the dihalocarbene adduct of that olefin dissolved in hexane. The dihalocarbene adduct would be expected to be reactive with silver nitrate if they were both in a homogenous solution but if the dihalocarbene adduct was in a saturated hydrocarbon solvent and the silver nitrate was in water, they might not come into sufficient contact to react. It might also be a problem for complex formation if the olefin that one sought to complex was itself not sufficiently soluble in water to allow reaction.

Use in Column Chromatography

Olefin containing compounds are separated on reverse phase columns when silver nitrate is dissolved in the mobile phase. It would be interesting to see whether the reverse phase HPLC mobility of unsaturated compounds in an aqueous silver nitrate eluate might give an indication of their complexing ability.

Liquid-liquid Extraction

Silver nitrate in methanol improves the separation of saturated fatty acids from unsaturated acids that can be held in solution better when silver nitrate is added. This suggests the possibility of liquid-liquid extraction between pentane or hexane and aqueous silver nitrate.