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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.

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