Claisen’s Alkali Reagent for Separating Very Weak Acids such as Enols and Cryptophenols

A Cryptophenol

One of the goals of the Kilomentor blog is to reinforce awareness of some of the simple, but robust, methods of isolation which have been used more frequently in the past but that can easily be scaled up.

Claisen’s alkali is made by dissolving 35 g of potassium hydroxide pellets (itself 85% potassium hydroxide and 15% water) in 25 ml of water with vigorous stirring and simultaneous external ice-cooling, followed by dilution with 100 ml of methanol and repeated cooling.  It is necessary to be thorough with the cooling because otherwise the base will probably react with the carbon dioxide in the air and weaken itself.

Claisen’s alkali is a powerful base solution that dissolves organic substrates sufficiently well so that the rate of deprotonation is rapid. At the same time, the liquid is immiscible and unreactive with saturated hydrocarbon solvents. Weak hydrophobic phenols and enols can be extracted out of hydrocarbon solution by contacting them with Claisen’s alkali. Thus, for example, 2,4,6-triallylphenol, which is insoluble in aqueous alkali can be extracted from petroleum ether with Claisen’s alkali. As another example, Vitamin K1 is easily isolated from 3-5% alfalfa concentrate by shaking an alcoholic suspension of the oil with aqueous sodium hydrosulfite to reduce all quinones to the hydroquinone state, then extracting with petroleum ether to take up all the hydrophobic solutes and then extracting this with Claisen’s alkali.  The extract is yellow from the formation of potassium anions and dianions. By dilution of the alcoholic solution with water even without acidification the K1 hydroquinone can be extracted back into ether and isolated from there.  The back extraction into ether works even without acidification because the hydrophobic hydroquinone in aqueous solution hydrolyzes enough to be taken up into ether and this drives the hydrolysis according to Le Chatelier’s Principle.

Lipophilic primary and secondary sulfonamides can also be separated from other substances that lack weakly acid hydrogens using Claisen’s alkali extraction of a pet. ether solution.  The key is that the sulfonamides must be sufficiently large and hydrophobic to dissolve in the pet. ether.

There is no study that I know that teaches what compounds can be taken up in Claisen’s alkali. At the very least it seems that a hydrogen on carbon needs to be activated by at least one carbonyl and one double bond.  In another well-known example exhaustive dichromate oxidation of cholesterol and removal of extensive acidic fractions by a simple aqueous base extraction leaves a mixture of delta 4 cholestene-3,6-dione and several monoketones and other neutral products (Org. Syn. Coll. Vol. 4, 189 (1963)). Repeated extraction of a solution of this mixture in pet. ether with Claisen’s alkali as long as the extracts are colored yellow (note the simple visual test of effectiveness) affords a simple means of isolating the total enedione present, which in this case is 40%.

Compounds which are so weakly acidic that they cannot be extracted by basic aqueous solution but which can be captured into Claisen’s alkali are termed cryptophenols, a descriptive term that is not however widely known or used. Molecules in which a methylene is substituted by two moderately electron-withdrawing groups would be candidates for Claisen’s alkali extraction.