Inorganic chemistry, anacyl chloride (oracid chloride) is anorganic compound with thefunctional group−C(=O)Cl. Their formula is usually writtenR−COCl, where R is aside chain. They are reactive derivatives ofcarboxylic acids (R−C(=O)OH). A specific example of an acyl chloride isacetyl chloride,CH3COCl. Acyl chlorides are the most important subset ofacyl halides.
Where the acyl chloridemoiety takes priority, acyl chlorides are named by taking the name of the parent carboxylic acid, and substituting-yl chloride for-ic acid. Thus:
(Idiosyncratically, for some trivial names,-oyl chloride substitutes-ic acid. For example, pivalic acid becomes pivaloyl chloride and acrylic acid becomes acryloyl chloride. The names pivalyl chloride and acrylyl chloride are less commonly used, although they are arguably more logical.)
When other functional groups take priority, acyl chlorides are considered prefixes —chlorocarbonyl-:[1]
Lacking the ability to formhydrogen bonds, acyl chlorides have lower boiling and melting points than similarcarboxylic acids. For example, acetic acid boils at 118 °C, whereas acetyl chloride boils at 51 °C. Like mostcarbonyl compounds,infrared spectroscopy reveals a band near 1750 cm−1.
The simplest stable acyl chloride is acetyl chloride; formyl chloride is not stable at room temperature, although it can be prepared at –60 °C or below.[2][3]
Acyl chlorides hydrolyze (react with water) to form the corresponding carboxylic acid andhydrochloric acid:
The industrial route to acetyl chloride involves the reaction ofacetic anhydride withhydrogen chloride:[5]
Propionyl chloride is produced by chlorination ofpropionic acid withphosgene:[6]
Benzoyl chloride is produced by the partial hydrolysis ofbenzotrichloride:[7]
Similarly, benzotrichlorides react with carboxylic acids to the acid chloride. This conversion is practiced for the reaction of1,4-bis(trichloromethyl)benzene to giveterephthaloyl chloride:
In the laboratory, acyl chlorides are generally prepared by treating carboxylic acids withthionyl chloride (SOCl2).[8] The reaction is catalyzed bydimethylformamide 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:
Another method involves the use ofoxalyl chloride:
The reaction is catalysed bydimethylformamide (DMF), which reacts with oxalyl chloride to give theVilsmeier reagent, an iminiumintermediate that which reacts with the carboxylic acid to form a mixed imino-anhydride. This structure undergoes anacyl 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 ofbenzoyl chloride andacetic acid:[9]
Other methods that do not form HCl include theAppel reaction:[16]
Another is the use ofcyanuric chloride:[17]
Acyl chloride are reactive, versatile reagents.[18] Acyl chlorides have a greater reactivity than other carboxylic acid derivatives like acidanhydrides,esters oramides:
Acyl chlorides hydrolyze, yielding the carboxylic acid:
This hydrolysis is usually a nuisance rather than intentional.
Acid chlorides are useful for the preparation of amides, esters, anhydrides. These reactions generate chloride, which can be undesirable. Acyl chlorides are used to prepareacid anhydrides,amides andesters, by reacting acid chlorides with: a salt of acarboxylic acid, anamine, or analcohol, respectively.
Acid halides are the most reactive acyl derivatives, and can easily be converted into any of the others. Acid halides will react with carboxylic acids to form anhydrides. If the structure of the acid and the acid chloride are different, the product is a mixed anhydride. First, the carboxylic acid attacks the acid chloride (1) to give tetrahedral intermediate2. The tetrahedral intermediate collapses, ejecting chloride ion as the leaving group and formingoxonium species3. Deprotonation gives the mixed anhydride,4, and an equivalent of HCl.
Alcohols andamines react with acid halides to produceesters andamides, respectively, in a reaction formally known as theSchotten-Baumann reaction.[19] Acid halides hydrolyze in the presence of water to produce carboxylic acids, but this type of reaction is rarely useful, since carboxylic acids are typically used to synthesize acid halides. Most reactions with acid halides are carried out in the presence of a non-nucleophilic base, such aspyridine, to neutralize the hydrohalic acid that is formed as a byproduct.
The alcoholysis of acyl halides (the alkoxy-dehalogenation) is believed to proceed via anSN2 mechanism (Scheme 10).[20] However, the mechanism can also be tetrahedral orSN1 in highly polar solvents[21] (while the SN2 reaction involves a concerted reaction, the tetrahedral addition-elimination pathway involves a discernible intermediate).[22]
Bases, such aspyridine orN,N-dimethylformamide, catalyzeacylations.[14][10] These reagents activate the acyl chloride via a nucleophilic catalysis mechanism. The amine attacks the carbonyl bond and presumably[23] 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 theSchotten-Baumann reaction. This approach is used in the preparation of nylon via the so-callednylon rope trick.[24]
Acid halides react with carbon nucleophiles, such asGrignards andenolates, although mixtures of products can result. While a carbon nucleophile will react with the acid halide first to produce a ketone, the ketone is also susceptible to nucleophilic attack, and can be converted to a tertiary alcohol. For example, whenbenzoyl chloride (1) is treated with two equivalents of a Grignard reagent, such as methyl magnesium bromide (MeMgBr), 2-phenyl-2-propanol (3) is obtained in excellent yield. Althoughacetophenone (2) is an intermediate in this reaction, it is impossible to isolate because it reacts with a second equivalent of MeMgBr rapidly after being formed.[25]
Unlike most other carbon nucleophiles, lithium dialkylcuprates – often calledGilman reagents – can add to acid halides just once to give ketones. The reaction between an acid halide and a Gilman reagent is not a nucleophilic acyl substitution reaction, however, and is thought to proceed via a radical pathway.[26] TheWeinreb ketone synthesis can also be used to convert acid halides to ketones. In this reaction, the acid halide is first converted to an N–methoxy–N–methylamide, known as a Weinreb amide. When a carbon nucleophile – such as a Grignard ororganolithium reagent – adds to a Weinreb amide, the metal ischelated by the carbonyl and N–methoxy oxygens, preventing further nucleophilic additions.[27]
Carbon nucleophiles such asGrignard reagents, convert acyl chlorides toketones, which in turn are susceptible to the attack by second equivalent to yield the tertiaryalcohol. The reaction of acyl halides with certainorganocadmium reagents stops at the ketone stage.[28] The reaction withGilman reagents also afford ketones, reflecting the low nucleophilicity of these lithium diorganocopper compounds.[14]
Acyl chlorides are reduced bylithium aluminium hydride anddiisobutylaluminium hydride to give primary alcohols.Lithium tri-tert-butoxyaluminium hydride, a bulky hydride donor, reduces acyl chlorides to aldehydes, as does theRosenmund reduction usinghydrogen gas over a poisoned palladium catalyst.[29]
In theFriedel–Crafts acylation, acid halides act as electrophiles forelectrophilic aromatic substitution. ALewis acid – such aszinc chloride (ZnCl2),iron(III) chloride (FeCl3), oraluminum chloride (AlCl3) – coordinates to the halogen on the acid halide, activating the compound towards nucleophilic attack by anactivated aromatic ring. For especially electron-rich aromatic rings, the reaction will proceed without a Lewis acid.[30][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 givetransition metal acyl complexes. Illustrative is theoxidative addition ofacetyl chloride toVaska's complex, converting square planar Ir(I) to octahedral Ir(III):[31]
Low molecular weight acyl chlorides are oftenlachrymators, and they react violently with water, alcohols, and amines.
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