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] phosphorus pentachloride (PCl₅) or oxalyl chloride²⁷⁠ ([COCl]₂):[9][10]

3 RCO₂H + PCl₃ → 3 RCOCl + H₃PO₃

RCO₂H + PCl₅ → RCOCl + POCl₃ + HCl

Thionyl chloride[11]⁠ is a well-suited reagent as all the by-products (HCl, SO₂) are gases and residual thionyl chloride can be easily removed as a result of its low boiling point (76 °C). Relative to thionyl chloride, oxalyl chloride is more expensive but also a milder reagent and therefore more selective. Acyl bromides and iodides are synthesized accordingly but are less common.[12]

The reaction with thionyl chloride may be catalyzed by dimethylformamide.[13] 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.

Another method involves the use of oxalyl chloride:

RCO₂H + ClCOCOCl → RCOCl + CO + CO₂ + HCl

The reaction is catalysed by dimethylformamide (DMF), which reacts with oxalyl chloride in the first step to give an iminium intermediate, which reacts with the carboxylic acid, abstracting an oxide, and regenerating the DMF catalyst.[13]

Acid chlorides can be used as a chloride source.[14]

Other methods that do not form HCl include the Appel reaction:[15]

RCO₂H + Ph₃P + CCl₄ → RCOCl + Ph₃PO + HCCl₃

Another is the use of cyanuric chloride:[16]

RCO₂H + C₃N₃Cl₃ → RCOCl + C₃N₃Cl₂OH

Acyl chlorides react with water yielding the carboxylic acid:

This hydrolysis is usually a nuiscance rather than intentional. Acyl chlorides are used to prepare acid anhydrides, amides and esters, by reacting acid chlorides with: a salt of a carboxylic acid, an amine, or an alcohol, respectively.

The use of a base, e.g. aqueous , is desirable to remove the hydrogen chloride byproduct, and to catalyze the reaction. During the nucleophilic substitution, the equilibrium can be shifted towards the product by capturing the hydrogen chloride with a base such as dilute sodium hydroxide solution or a basic solvent like pyridine or N,N-dimethylformamide.[10]

The use of dilute sodium hydroxide solution results in formation of two phases (aqueous/organic): this type of reaction is called Schotten-Baumann reaction. Both pyridine as solvent and the two-phase reaction are used in the synthesis of polyesters and polyamides (e. g. for the so-called nylon rope trick[17]⁠).

Amines like pyridine catalyse the reaction of the acyl chlorides via an nucleophilic catalysis mechanism. The amine attacks the carbonyl bond and presumably[18]⁠ forms first a transient tetrahedral intermediate and afterwards, by the displacement of the leaving group, a quaternary acylammonium salt. This quaternary acylammonium salt is more susceptible to attack by alcohols or other nucleophiles.

Excess amine may be used as catalyst when preparing amides.[13]

With carbon nucleophiles such as Grignard reagents, acyl chlorides generally give the ketone, which is susceptible to the attack by second equivalent to yield the tertiary alcohol. The reaction of acyl halides with certain organocadmium reagents stops at the ketone stage, although cadmium compounds are highly toxic and carcinogenic.[19][20] The nucleophilic reaction with Gilman reagents also afford ketones, reflecting the low reactivity to these lithium diorganocopper compounds.[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.[21]

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.

Carboxylic acid halides are among the most reactive and versatile compounds in organic chemistry, and the full range of possible reactions has been reviewed.[22] Acyl chlorides have a greater reactivity than other carboxylic acid derivatives like acid anhydrides, esters or amides:

Acid chlorides can therefore be used to synthesize all compounds listed as being of lower reactivity. The high reactivity of the acid chloride is based on the chloride ion being a weak base and an excellent leaving group so that even weak nucleophiles attack the carbonyl group. When compared to its parent compound (the carboxylic acid) the higher reactivity can be explained by the hydroxyl group being a much worse leaving group.

The alcoholysis of acyl halides (the alkoxy-dehalogenation) is believed to proceed via an S_N2 mechanism (Scheme 10).[23]⁠ However, the mechanism can also be tetrahedral or S_N1 in highly polar solvents[24]⁠ (while the S_N2 reaction involves a concerted reaction, the tetrahedral addition-elimination pathway involves a discernible intermediate).[25]

Mechanism of ester formation via the alcoholysis of an acyl chloride.