The Potential Use of Acetic Anhydride/Acetic Acid for Enabling Solvent Switches during Work-Ups

Each reaction in a chemical process has solvents in which the conversions works better and the preferred solvents for consecutive reactions in a scheme are usually different. As a consequence, performing solvent switches is essential for telescoping process steps thereby avoiding unnecessary intermediate isolations.

The boiling points of acetic acid and acetic anhydride are respectively 117 and 140 C. Both acetic acid and acetic anhydride are quite inexpensive and they are biologically trouble-free.

Acetic acid is infinitely miscible with water and is an excellent solvent for broad classes of substrates. Mixed solutes dissolved in acetic acid lead upon water addition to decreasing solubility of most organic compounds.

Acetic anhydride is a solvent that reacts with solute molecules that have nucleophilic functionalities and particularly those with what is termed 'active hydrogens'. Because of its even higher boiling point, acetic anhydride can chase many lower boiling solvents during distillation. It can then be, itself, converted by hydrolysis to acetic acid, optionally neutralized with aqueous alkali, and washed away from lipophilic materials. Heating a solvent mixture in which acetic anhydride is a constituent dries it. Only enough acetic anhydride needs to be added to a crude product to provide liquidity, then distillation instituted until all the first reaction solvent has been removed. Even if an acetate ester or amide is formed during isolation, that can be reversed by alkaline hydrolysis after the solvent of the first reaction is removed.

Because acetic anhydride has a bp of 140 C, it can chase many different first solvents. Just considering those that boil above 60 C they include diisopropyl ether, pet. ether, carbon tetrachloride, butyl chloride, methyl ethyl ketone, benzene, cyclohexane, chlorobenzene, acetonitrile, methyl chloroacetate, 2-nitropropane, MIBK, nitroethane, toluene, 1,1,2-trichloroethane, trifluorotoluene, 1,4-dioxane, nitromethane,  methylcyclohexane, heptane, propionitrile, cyclohexene, 1,2-dichloroethane,  fluorobenzene, 1,2-dimethoxyethane, 1,1-diethoxymethane, trichloroethylene, tetrachloroethylene, dimethylcarbonate, and diethylcarbonate.

 

Consider for example acetic anhydride’s potential for changing from the high boiling solvent chlorobenzene to ethyl acetate. In such a scenario, a mixture of chlorobenzene and acetic anhydride could be distilled to remove chlorobenzene and some acetic anhydride. The still-pot residue would comprise acetic anhydride and non-volatile reaction mixture components. This residue does not solidify because of the presence of the acetic anhydride. The minimum stirrable volume is maintained. Water is added along with the new second solvent which must be water-immiscible, in this case, ethyl acetate. Dilute mineral acid or base may be added to accelerate hydrolysis of the acetic anhydride. The acetic acid or acetate anion dissolves in the aqueous phase and is cut away. The reaction mixture is left dissolved in ethyl acetate.

In a different scenario, if the first solvents are low enough boiling, acetic acid itself can serve as the chase liquid for distilling away the first solvent. The product may not be particularly soluble anhydrous acetic acid or the acetic acid can be subsequently diluted with water used as an anti-solvent to cause precipitation or the acetic acid can be optionally neutralized and washed away with water after adding the new water-immiscible second solvent.

Acetic acid itself forms azeotropes with many common solvents that reduce the temperature at which they can be removed: butyl ether, chlorobenzene, cyclohexane, cyclohexane, tetrachloroethylene, trichloroethylene, toluene and xylene are among these.