Reactivity

Acyl halides are the most reactive of all the carboxylic acid derivatives as explained by the negligible contribution of the resonance form with the positive charge on the L (halide) group.

Reactivity of acyl halides: with water they give acids, with alcohols esters, with amines amides, with carboxylates anhydrides, with cuprates ketones and with H₂/catalyst or LiAl(OR)₃H aldehydes

The mechanism is the usual addition-elimination process.

Addition–elimination mechanism of a nucleophile with an acyl halide: tetrahedral intermediate and loss of HX

The versatility of the acyl chloride function is pretty wide allowing its transformation into other very important functional groups.

Some of them will be introduced to you for the first time...

Hydrolysis and alcoholysis

Acyl halides can be converted into carboxylic acids with the mere contact with moisture. Therefore, one has to be very careful and store acyl halides in a dry and inert atmosphere (dry nitrogen or argon).

Acyl halides produce esters with alcohols. The reaction does require a base in order to capture the released HCl.

Selective acetylation of the OH of a hydroxy acid with acetyl chloride in pyridine; pyridinium chloride is formed

Phosgene is kind of "double" acyl halide from formic acid and can react with an alcohol excess to yield carbonates. If the amount of alcohol is controlled to just one equivalent, only one chloride is consumed and the remaining one can further react with amines rendering carbamates.

Phosgene with excess alcohol gives carbonates, and with one equivalent of alcohol gives chloroformates, which with amines give carbamates, protecting groups of amines

Ammonia and amines

Ammonia and primary or secondary amines (not tertiary!) lead to amides. The amine in excess is able to neutralize the released HCl.

Benzoyl chloride with excess ammonia gives benzamide and ammonium chloride

Benzoyl chloride with excess dimethylamine gives N,N-dimethylbenzamide

ISOCYANATES (R-N=C=O) bear a functional group related to carboxylic acid derivatives. They can be prepared from phosgene and primary amines, going through an intermediate that possesses an acyl chloride Cl-C=O group.

Phosgene with aniline gives a carbamoyl chloride that loses HCl to form phenyl isocyanate

Organometallics

Covalent and low reactive organometallics render ketones with acyl chlorides. An excellent example is the use of lithium alkylcuprates.

Benzoyl chloride with a diisopropenyl cuprate gives an α,β-unsaturated ketone

Recall here lithium alkylcuprates within the context of conjugated addition to α,β-unsaturated carbonyls (Michael addition).

Did you wonder why organolithium or organomagnesium (Grignard) cannot be used to carry out this reaction?

Low-Reactivity hydrides

"Deactivated" hydrides are able to undergo the formal replacement of chloride by hydride on acyl chlorides leading to aldehydes.

LiAlH₄ with three equivalents of tert-butanol gives LiAl(t-BuO)₃H, a hindered hydride

Selective reduction of an acid chloride to an aldehyde with LiAl(t-BuO)₃H without affecting the ester

Many functional groups endure these mild reduction conditions.

Why LiAlH₄ cannot be used for the same purpose?

Hydrogenation with the Lindlar catalyst

Do you remember Lindlar catalyst? Partially poisoned Pd with quinoline and other additives. The hydrogenation of acyl chlorides using this catalyst yields aldehydes as well.

Hydrogenation with Lindlar catalyst: the acid chloride becomes an aldehyde and the triple bond a double bond

Click here to remember the partial reduction of alkynes to alkenes with Lindlar catalyst.

Aromatic compounds (Friedel-Crafts acylation)

Do you remember that this reaction avoided the problems associated to carbocations when one attempted to link an alkyl chain to an aromatic ring? This reaction led to aryl ketones.

Click here to review the SEAr reaction (Friedel-Crafts acylation).

Friedel–Crafts acylation of benzene with an acyl halide or anhydride and AlCl₃ to give an aryl ketone

Other reactions (Arndt-Eistert reaction and dehydrohalogenation)

Arndt-Eistert reaction:
Diazomethane is able to react with acyl chlorides giving diazoketones, very reactive species that in weak oxidizing conditions rearrange yielding esters.

Arndt–Eistert homologation: benzoyl chloride with diazomethane gives a diazoketone, which with Ag₂O in ethanol gives ethyl phenylacetate

Click here to find other uses of diazomethane.

The result of the reaction is the formal insertion of a CH₂ group between the carbonyl and the R group formerly bonded to it. This process is named homologation of carboxylic acid derivatives. Its mechanism is very complex but a very good exercise in the learning of Organic Chemistry.

Mechanism of the Arndt–Eistert synthesis: formation of the diazoketone, Wolff rearrangement to the ketene and addition of water to give the homologous acid

Tertiary amines cannot produce amides by reaction with acyl chlorides but their high basicity allow them to capture a molecule of HCl and transform acyl chlorides into ketenes (R–CH=C=O).

Important: For this reaction to proceed it is essential that the acyl chloride has at least one α hydrogen.

Phenylacetyl chloride with triethylamine loses HCl to give phenylketene