Acyl Chloride
   HOME

TheInfoList



OR:

In
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
, an acyl chloride (or acid chloride) is an
organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...
with the
functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
. Their formula is usually written , where R is a
side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
. They are reactive derivatives of
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
s (). A specific example of an acyl chloride is acetyl chloride, . Acyl chlorides are the most important subset of acyl halides.


Nomenclature

Where the acyl chloride moiety takes priority, acyl chlorides are named by taking the name of the parent carboxylic acid, and substituting ''-yl chloride'' for ''-ic acid''. Thus: : : : butyr''ic acid'' (C3H7COOH) → butyr''yl chloride'' (C3H7COCl) (Idiosyncratically, for some trivial names, ''-oyl chloride'' substitutes ''-ic acid''. For example, pival''ic acid'' becomes pival''oyl chloride'' and acryl''ic acid'' becomes acryl''oyl 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-'': :


Properties

Lacking the ability to form
hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...
s, acyl chlorides have lower boiling and melting points than similar
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
s. For example, acetic acid boils at 118 °C, whereas acetyl chloride boils at 51 °C. Like most carbonyl 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. Acyl chlorides hydrolyze (react with water) to form the corresponding carboxylic acid and
hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...
: :RCOCl + H2O -> RCOOH + HCl


Synthesis


Industrial routes

The industrial route to acetyl chloride involves the reaction of acetic anhydride with
hydrogen chloride The Chemical compound, compound hydrogen chloride has the chemical formula and as such is a hydrogen halide. At room temperature, it is a colorless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapor. Hyd ...
: :(CH3CO)2O + HCl -> CH3COCl + CH3CO2H Propionyl chloride is produced by chlorination of
propionic acid Propionic acid (, from the Greek language, Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula . It is a ...
with phosgene: :CH3CH2CO2H + COCl2 -> CH3CH2COCl + HCl + CO2 Benzoyl chloride is produced by the partial hydrolysis of benzotrichloride: :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: :C6H4(CCl3)2 + C6H4(CO2H)2 -> 2 C6H4(COCl)2 + 2 HCl


Laboratory methods


Thionyl chloride

In the laboratory, acyl chlorides are generally prepared by treating carboxylic acids with thionyl chloride (). The reaction is catalyzed by
dimethylformamide Dimethylformamide, DMF is an organic compound with the chemical formula . Its structure is . Commonly abbreviated as DMF (although this initialism is sometimes used for 2,5-dimethylfuran, dimethylfuran, or dimethyl fumarate), this colourless liqui ...
and other additives. Thionyl chloride⁠ is a well-suited reagent as the by-products (HCl, ) are gases and residual thionyl chloride can be easily removed as a result of its low boiling point (76 °C).


Phosphorus chlorides

Phosphorus trichloride () is popular, although excess reagent is required. Phosphorus pentachloride () is also effective, but only one chloride is transferred: :RCO2H + PCl5 -> RCOCl + POCl3 + HCl


Oxalyl chloride

Another method involves the use of oxalyl chloride: :RCO2H + ClCOCOCl -> MF RCOCl + CO + CO2 + HCl The reaction is catalysed by
dimethylformamide Dimethylformamide, DMF is an organic compound with the chemical formula . Its structure is . Commonly abbreviated as DMF (although this initialism is sometimes used for 2,5-dimethylfuran, dimethylfuran, or dimethyl fumarate), this colourless liqui ...
(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. Relative to thionyl chloride, oxalyl chloride is more expensive but also a milder reagent and therefore more selective. :


Other laboratory methods

Acid chlorides can be used as a chloride source. Thus acetyl chloride can be distilled from a mixture of benzoyl chloride and
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
: :CH3CO2H + C6H5COCl -> CH3COCl + C6H5CO2H Other methods that do not form HCl include the Appel reaction: :RCO2H + Ph3P + CCl4 -> RCOCl + Ph3PO + HCCl3 Another is the use of cyanuric chloride: :RCO2H + C3N3Cl3 -> RCOCl + C3N3Cl2OH


Reactions

Acyl chloride are reactive, versatile reagents. Acyl chlorides have a greater reactivity than other carboxylic acid derivatives like acid anhydrides,
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s or
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s: ::: Acyl chlorides hydrolyze, yielding the carboxylic acid: ::: This hydrolysis is usually a nuisance rather than intentional.


Alcoholysis, aminolysis, and related reactions

Acid chlorides are useful for the preparation of amides, esters, anhydrides. These reactions generate chloride, which can be undesirable. Acyl chlorides are used to prepare acid anhydrides,
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s and
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s, by reacting acid chlorides with: a salt of a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
, an
amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
, or an
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
, 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 intermediate 2. The tetrahedral intermediate collapses, ejecting chloride ion as the leaving group and forming oxonium species 3. Deprotonation gives the mixed anhydride, 4, and an equivalent of HCl. Alcohols and
amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
s react with acid halides to produce
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s and
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...
s, respectively, in a reaction formally known as the Schotten-Baumann reaction. 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 as pyridine, to neutralize the hydrohalic acid that is formed as a byproduct.


Mechanism

The alcoholysis of acyl halides (the alkoxy-dehalogenation) is believed to proceed via an SN2 mechanism (Scheme 10).⁠ However, the mechanism can also be tetrahedral or SN1 in highly polar solvents⁠ (while the SN2 reaction involves a concerted reaction, the tetrahedral addition-elimination pathway involves a discernible intermediate). Bases, such as pyridine or ''N,N''-dimethylformamide, catalyze acylations. These reagents activate the acyl chloride via a nucleophilic catalysis mechanism. The amine attacks the carbonyl bond and presumably⁠ 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''.⁠


Reactions with carbanions

Acid halides react with carbon nucleophiles, such as Grignards and enolates, 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, when benzoyl 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. Although acetophenone (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. Unlike most other carbon nucleophiles, lithium dialkylcuprates – often called Gilman 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. The Weinreb 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 or organolithium reagent – adds to a Weinreb amide, the metal is chelated by the carbonyl and N–methoxy oxygens, preventing further nucleophilic additions. Carbon nucleophiles such as Grignard reagents, convert acyl chlorides to
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
s, which in turn are susceptible to the attack by second equivalent to yield the tertiary
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
. The reaction of acyl halides with certain organocadmium reagents stops at the ketone stage. The reaction with Gilman reagents also afford ketones, reflecting the low nucleophilicity of these lithium diorganocopper compounds.


Reduction

Acyl chlorides are reduced by lithium aluminium hydride and
diisobutylaluminium hydride Diisobutylaluminium hydride (DIBALH, DIBAL, DIBAL-H or DIBAH) is a reducing agent with the chemical formula, formula (''i''-Bu2AlH)2, where ''i''-Bu represents isobutyl (-CH2CH(CH3)2). This organoaluminium chemistry, organoaluminium compound is a r ...
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.


Acylation of arenes

In the Friedel–Crafts acylation, acid halides act as electrophiles for electrophilic aromatic substitution. A
Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
– such as
zinc chloride Zinc chloride is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula ZnCl2·''n''H2O, with ''n'' ranging from 0 to 4.5, forming water of hydration, hydrates. Zinc chloride, anhydrous and its hydrates, are colo ...
(ZnCl2), iron(III) chloride (FeCl3), or aluminum chloride (AlCl3) – coordinates to the halogen on the acid halide, activating the compound towards nucleophilic attack by an activated aromatic ring. For especially electron-rich aromatic rings, the reaction will proceed without a Lewis acid.Kürti and Czakó 2005, p. 176. : 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.


Oxidative addition

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): :IrCl(CO)(PPh3)2 + CH3COCl -> CH3COIrCl2(CO)(PPh3)2


Hazards

Low molecular weight acyl chlorides are often lachrymators, and they react violently with water, alcohols, and amines.


References

{{Authority control Functional groups