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Quality synthetic chemists these days are more easily differentiated from the average by their ability to devise efficient isolations, particularly isolations that are rugged enough to work on scale up. Substructure, reaction and citation searching have simplified the art of the constructing the synthetic path itself.

Although there exist many methods to separate a mixture into acid, base and neutral fractions, and even to separate mixed bases or acids using of their relative proton donor/proton acceptor abilities, the vast majority of organic substances are essentially neutral. Therefore, methods that can separate the neutral fraction into sub-fractions in a simple fashion are valuable.

The only separations of aldehydes and ketones from other neutral functional group classes which is quickly recalled by the average chemist is sodium bisulfite for aldehydes and Girard’s P and T reagents for all carbonyls. Kilomentor, in another blog article, has discussed the use of the Okomoto reagent for aldehydes.

R.P. Singh, H. N. Subbarao and Sukh Dev, Tetrahedron 37, 843 (1981) have written a paper subtitled, Silica-Gel Supported Reagents for the Isolation of Aldehydes and Ketones. This technique, as they teach, works only for neutral carbonyl containing fractions that are fully soluble in hexane, toluene or other non-polar media, because it is necessary that the non-aldehyde/non-ketone fraction remain dissolved in the non-polar solvent during the method. This requirement is easily met, since the neutral fraction can be first partitioned between the non-polar solvent (preferable hexane or cyclohexane) and methanol/water or acetonitrile.

In the technique the neutral fraction to be separated is dissolved in the non-polar solvent and treated with an appropriate amount of 10%w/w semicarbazide on silica-gel. The mixture is heated and stirred at 70 C for 12-18 hours. As the carbonyl components in the mixture react with the semicarbazide they become immobilized on the insoluble solid silica gel phase. The end of reaction is detected by the absence of carbonyl compound in the solution phase as measured by TLC developed with 10% 2,4-DNPH in aq. Aq. HCl. When the reaction is complete the mixture is cooled, filtered and the solid washed with the same solvent used in the adsorption step. The combined filtrate and washing that contain the non-aldehyde/non ketone fraction are processed or discarded as the overall isolation process requires. The solid phase containing the semi-carbazone (if it contains about 1 mmole) is added to a solution of about 10 mmoles of oxalic acid in 16 ml of water, covered with a layer of immiscible organic solvent and the mixture stirred and refluxed for 4-5 hours. The solid is separated, washed; the aqueous phase is extracted and all the organic layers combined. The aldehydes and ketones can be found within this phase.

The authors report that this method has been used with good effect to separate almost a kilogram of neutral natural product extract containing 90 gm of carbonyl fraction.

The method can also be used to separate a small amount of carbonyl impurity from a large amount of non-carbonyl product. Such a separation would be even more applicable to large scale since the amount of reagent adsorbed on silica gel would be smaller.

The Semi-Carbazide on Silica Gel Reagent is prepared as follows:

Semicarbazide hydrochloride (5.0g; 0.045 moles) was added to a solution of sodium hydroxide (2.0 g: 0.05 mole) in water-methanol (1:1; 60 ml) and to the resulting clear solution, silica gel (45 gm) was introduced with stirring. The whole mixture was mechanically shaken (1 hr) at room temperature (3- 35 C; India) and water-methanol removed on a rotary evaporator (about 90 C/80-90 mm; 30-45 min) to get a free flowing powder. This material should weigh 60-63 g. The product is stored in a brown bottle at room temp. A two-year old product did not undergo deterioration.

This very widely applicable methodology has been only little applied. A citation search would show how little. The only reference that I am very familiar with is the Masters thesis of Tarcisia Khomasurya from the University of Toronto Canada. Khomasurya applied the reagent to the separation of the ketone from the non-carbonyl components of cedar oil. For natural product mixtures the preferred reaction solvent is cyclohexane because it can be easily thoroughly purified so it does not put impurities into the fractions.

Expired US patents 4,332,968 and 4,306,068 contain a chemical trick that can be used to remove water from many wet liquids. Apparently if mesityl oxide, (Me)₂C=CH-CO-Me, is added to the wet liquid in the stoichiometry of 1 mole of mesityl oxide for each mole of water and a catalytic amount of a primary amine is added and the liquid is then warmed up two equivalents of acetone will form as the acetone is distilled out of the mixture.

The mechanism of the process has been studied by Ralph M. Pollack and David Strohbeen, J. Am. Chem.. Soc. (1972), 94(7), 2534-5. One can imagine that the method could be used to de-water liquids that are difficult to dry by other means such as DMSO, DMF, etc. The method would certainly efficiently dry lower molecular weight water-miscible primary amines, where the catalyst would be present in enormous excess.

The two patents are directed to other very practical uses. Reaction of a mixture of a primary and a non-primary amine by heating the mixture together with mesityl oxide results in a mixture of the imine of the primary amine with acetone, and unreacted non-primary amine. The patents teach that where the amine mixture cannot be separated by distillation, the new mixture of imine and non-primary amine usually can be.

Another use claimed by these lapsed patents is a means to make the imine quantitatively as a protecting group for the primary amine.

It is not known what range of other functional groups can be tolerated by this method which destroys water by converting it to acetone, but the possibilities are large. As far as I can tell, this methodology has not been used outside of these publications. Of course, one of the problems with process patents is that the users do not publicize that they have been infringing the monopoly.

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 has a free phenol and the other a phenol ether. If one puts the mixture into a two phase mixture of say toluene and water, adds sodium hydroxide to the water and stirs the phases gently, then after some time the phenolic ester will be found transferred to the aqueous base phase, where the ester has hydrolysed to the carboxylate, while the ether-ester is untouched in the toluene phase.

I have used this trick several times. It works because the free phenol increases the solubility of its ester substrate slightly in the water and once in the water, its ester is quickly hydrolysed. As the sodium carboxylate it is stuck quantitatively in the water. The ether -ster on the other hand is essentially 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.

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