Acid Traps & Acid Acceptors for Use in Organic Reactions to Remove any strongly Acidic Coproduct

 

If a chemical reaction produces as a co-product a small strongly-acidic molecule, the equilibrium of that reaction can be disturbed towards a more complete reaction by trapping that coproduct. The following agents have potential to do this:

Pyridine

2,6-Lutidine

2,6-Di-t-butylpyridine

Poly4-vinylpyridines

Urea

Tetramethylurea

Acetamide forms HBr complex the is insoluble in many organic solvents

Magnesium oxide

Sodium acetate

Calcium carbonate

Mercuric oxide

Ammonium  acetate

Ammonium formate

1,2-epoxy-3-phenoxypropane

Ethylene oxide

Propylene oxide

Epichlorohydrin

Ethylenediamine

Pentamethylpiperidine

1,8-Bis-dimethylamino-naphthalene (proton sponge)

Hexamethyldisiloxane

Trimethylsilyltrifluoroacetamide

Trimethylsilylurethane

4A Molecular sieves

Pyridine ion-exchange resin

Amino Acid Hydrochlorides to Give Zwitterions

N-alkyl-2 halopyridines, formamide acetals, 4A Molecular sieves

Silver oxide

Lead Hydroxide from Acetate: neutralizes acid and gives insoluble salts

Acid acceptors and acid traps typically neutralize or otherwise deactivate acid that is already present and most often that has been created as a coproduct in a reaction. By ‘tying up’ any acid co-product any reversible reaction that involves it is driven to completion and prevented from reversing in accordance with Le Chatelier’s Principle.

Typically acid traps are not bases themselves although all that is essential is that they be substantially less nucleophilic than the moiety that is required to be the nucleophile in the planned transformation. If the nucleophile which is the hoped-for participant in the chemical reaction is readily available and inexpensive the same species can serve in appropriate quantity both as nucleophile and acid trapping agent.

Sometimes the reaction that forms the acid co-product does not involve any nucleophile. Free-radical bromination comes to mind. In this instance, the acid trap must be not nucleophilic at all because it is going to be the strongest Lewis base in the mixture. A substance that forms an insoluble adduct, or which itself is insoluble, or which constitutes a separate phase or which irreversibly reacts with the acid is desirable. Proton sponge, pentamethylpiperidine, urea, N,N,N',N’-tetramethylurea, 2,6-di-t-butylpyridine are not nucleophilic.  Magnesium oxide and calcium carbonate are insoluble in organic solvents. Ammonium acetate and ammonium formate are inorganic neutralizing salts that are volatile and so can be pumped away under a vacuum. The four epoxide agents react with acid halides by opening to halohydrins. 

Hexamethyldisiloxane, trimethylsilyltrifluoroacetamide, and trimethylsilylurethane convert free hydrogen halide into trimethylsilylhalide. For this reason, they must be used in sufficient quantity to persilylate any other reactive functional groups in the molecules. Molecular sieves and basic ion exchange resins work by taking free acid into a different phase.

I have used a slightly different idea to remove excess HBr in a process step developed during my industrial career. I added t-butanol to my reaction. It rapidly reacted with HBr as it was formed giving water and non-acidic t-butylbromide.