Acyl chloride

The industrial route to acetyl chloride involves the reaction of acetic anhydride with hydrogen chloride:[4]

(CH₃CO)₂O + HCl → CH₃COCl + CH₃CO₂H

Propionyl chloride is produced by chlorination of propionic acid with phosgene:[5]

CH₃CH₂CO₂H + COCl₂ → CH₃CH₂COCl + HCl + CO₂

Benzoyl chloride is produced by the partial hydrolysis of benzotrichloride:[6]

C₆H₅CCl₃ + H₂O → C₆H₅C(O)Cl + 2 HCl

In the laboratory, acyl chlorides are generally prepared in the same manner as alkyl chlorides, by replacing the corresponding hydroxy substituents with chlorides. Thus, carboxylic acids are treated with thionyl chloride (SOCl₂),[7] phosphorus trichloride (PCl₃),[8] or phosphorus pentachloride (PCl₅):[9][10]

RCOOH + SOCl₂ → RCOCl + SO₂ + HCl

3 RCOOH + PCl₃ → 3 RCOCl + H₃PO₃

RCOOH + PCl₅ → RCOCl + POCl₃ + HCl

The reaction with thionyl chloride may be catalyzed by dimethylformamide.[11] In this reaction, the sulfur dioxide (SO₂) and hydrogen chloride (HCl) generated are both gases that can leave the reaction vessel, driving the reaction forward. Excess thionyl chloride (b.p. 74.6 °C) is easily evaporated as well.[10] The reaction mechanisms involving thionyl chloride and phosphorus pentachloride are similar; the mechanism with thionyl chloride is illustrative:[11]

Another method involves the use of oxalyl chloride:

RCOOH + ClCOCOCl → RCOCl + CO + CO₂ + HCl

The reaction is catalysed by dimethylformamide (DMF), which reacts with oxalyl chloride in the first step to give the iminium intermediate.

The iminium intermediate reacts with the carboxylic acid, abstracting an oxide, and regenerating the DMF catalyst.[11]

Finally, methods that do not form HCl are also known, such as the Appel reaction:[12]

RCOOH + Ph₃P + CCl₄ → RCOCl + Ph₃PO + HCCl₃

and the use of cyanuric chloride (C₃N₃Cl₃):[13]

Acyl chlorides react with water yielding the carboxylic acid:

RCOCl + H₂O → RCO₂H + HCl

Acyl chlorides are used to prepare acid anhydrides, esters, and amides by reacting acid chlorides with: a salt of a carboxylic acid, an alcohol, or an amine, respectively. The use of a base, e.g. aqueous sodium hydroxide or pyridine,[10] or excess amine (when preparing amides)[11] is desirable to remove the hydrogen chloride byproduct, and to catalyze the reaction. While it is often possible to obtain esters or amides from the carboxylic acid with alcohols or amines, the reactions are reversible, often leading to low yields. In contrast, both reactions involved in preparing esters and amides via acyl chlorides (acyl chloride formation from carboxylic acid, followed by coupling with the alcohol or amine) are fast and irreversible. This makes the two-step route often preferable to the single step reaction with the carboxylic acid.[10]

With carbon nucleophiles such as Grignard reagents, acyl chlorides generally react first to give the ketone and then with a second equivalent to the tertiary alcohol. A notable exception is the reaction of acyl halides with certain organocadmium reagents which stops at the ketone stage. The nucleophilic reaction with Gilman reagents (lithium diorganocopper compounds) also afford ketones, due to their lesser reactivity.[10] Acid chlorides of aromatic acids are generally less reactive those of alkyl acids and thus somewhat more rigorous conditions are required for reaction.

Acyl chlorides are reduced by lithium aluminium hydride and diisobutylaluminium hydride to give primary alcohols. Lithium tri-tert-butoxyaluminium hydride, a bulky hydride donor, reduces acyl chlorides to aldehydes, as does the Rosenmund reduction using hydrogen gas over a poisoned palladium catalyst.[14]

With Lewis acid catalysts like ferric chloride or aluminium chloride, acyl chlorides participate in Friedel-Crafts acylations, to give aryl ketones:[8][10]

Because of the harsh conditions and the reactivity of the intermediates, this otherwise quite useful reaction tends to be messy, as well as environmentally unfriendly.