Acyl chloride

The industrial route to acetyl chloride involves the reaction of acetic anhydride with hydrogen chloride:[5]

${\displaystyle {\ce {(CH3CO)2O + HCl -> CH3COCl + CH3CO2H}}}$

Propionyl chloride is produced by chlorination of propionic acid with phosgene:[6]

${\displaystyle {\ce {CH3CH2CO2H + COCl2 -> CH3CH2COCl + HCl + CO2}}}$

Benzoyl chloride is produced by the partial hydrolysis of benzotrichloride:[7]

${\displaystyle {\ce {C6H5CCl3 + H2O -> C6H5C(O)Cl + 2 HCl}}}$

Similarly, benzotrichlorides react with carboxylic acids to the acid chloride. This conversion is practiced for the reaction of 1,4-bis(trichloromethyl)benzene to give terephthaloyl chloride:

${\displaystyle {\ce {C6H4(CCl3)2 + C6H4(CO2H)2 -> 2 C6H4(COCl)2 + 2 HCl}}}$

In the laboratory, acyl chlorides are generally prepared by treating carboxylic acids with thionyl chloride (SOCl₂).[8] The reaction is catalyzed by dimethylformamide and other additives.[9][10]

Thionyl chloride[11]⁠ is a well-suited reagent as 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).

Phosphorus trichloride (PCl₃) is popular,[12] although excess reagent is required.[9] Phosphorus pentachloride (PCl₅) is also effective,[13][14] but only one chloride is transferred:

${\displaystyle {\ce {RCO2H + PCl5 -> RCOCl + POCl3 + HCl}}}$

Another method involves the use of oxalyl chloride:

${\displaystyle {\ce {RCO2H + ClCOCOCl ->[DMF] RCOCl + CO + CO2 + HCl}}}$

The reaction is catalysed by dimethylformamide (DMF), which reacts with oxalyl chloride to give the Vilsmeier reagent, an iminium intermediate that which reacts with the carboxylic acid to form a mixed imino-anhydride. This structure undergoes an acyl substitution with the liberated chloride, forming the acid anhydride and releasing regenerated molecule of DMF.[10] Relative to thionyl chloride, oxalyl chloride is more expensive but also a milder reagent and therefore more selective.

Acid chlorides can be used as a chloride source.[15] Thus acetyl chloride can be distilled from a mixture of benzoyl chloride and acetic acid:[9]

${\displaystyle {\ce {CH3CO2H + C6H5COCl -> CH3COCl + C6H5CO2H}}}$

Other methods that do not form HCl include the Appel reaction:[16]

${\displaystyle {\ce {RCO2H + Ph3P + CCl4 -> RCOCl + Ph3PO + HCCl3}}}$

Another is the use of cyanuric chloride:[17]

${\displaystyle {\ce {RCO2H + C3N3Cl3 -> RCOCl + C3N3Cl2OH}}}$

Acid chlorides are useful for the preparation of amides, esters, anhydrides. These reactions generate chloride, which can be undesirable. Acyl chlorides hydrolyze, yielding the carboxylic acid:

This hydrolysis is usually a nuisance 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 alcoholysis of acyl halides (the alkoxy-dehalogenation) is believed to proceed via an S_N2 mechanism (Scheme 10).[19]⁠ However, the mechanism can also be tetrahedral or S_N1 in highly polar solvents[20]⁠ (while the S_N2 reaction involves a concerted reaction, the tetrahedral addition-elimination pathway involves a discernible intermediate).[21]

Bases, such as pyridine or N,N-dimethylformamide, catalyze acylations.[14][10] These reagents activate the acyl chloride via a nucleophilic catalysis mechanism. The amine attacks the carbonyl bond and presumably[22]⁠ first forms a transient tetrahedral intermediate, then forms a quaternary acylammonium salt by the displacement of the leaving group. This quaternary acylammonium salt is more susceptible to attack by alcohols or other nucleophiles.

The use of two phases (aqueous for amine, organic for acyl chloride) is called the Schotten-Baumann reaction. This approach is used in the preparation of nylon via the so-called nylon rope trick.[23]⁠

Carbon nucleophiles such as Grignard reagents, convert acyl chlorides to ketones, which in turn are 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.[24] The reaction with Gilman reagents also afford ketones, reflecting the low nucleophilicity of these lithium diorganocopper compounds.[14]

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.[25]

The Rosenmund reduction

With Lewis acid catalysts like ferric chloride or aluminium chloride, acyl chlorides participate in Friedel-Crafts acylations, to give aryl ketones:[12][14]

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.

Acyl chlorides react with low-valent metal centers to give transition metal acyl complexes. Illustrative is the oxidative addition of acetyl chloride to Vaska's complex, converting square planar Ir(I) to octahedral Ir(III):[26]

${\displaystyle {\ce {IrCl(CO)(PPh3)2 + CH3COCl -> CH3COIrCl2(CO)(PPh3)2}}}$