The Friedel–Crafts reactions are a set of
reactions developed by
Charles Friedel and
James Crafts in 1877 to attach substituents to an
aromatic ring
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
. Friedel–Crafts reactions are of two main types:
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...
reactions and
acylation
In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent.
Because they form a strong electrophile when treated with ...
reactions. Both proceed by
electrophilic aromatic substitution
Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic n ...
.
Alkylation
With alkyl halides
Friedel–Crafts alkylation involves the
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...
of an
aromatic ring
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
. Traditionally, the alkylating agents are
alkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely us ...
s. Many alkylating agents can be used instead of alkyl halides. For example,
enones and
epoxide
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
s can be used in presence of protons. Traditionally also, the reaction employs a strong
Lewis acid, such as
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
as catalyst.
This reaction suffers from the disadvantage that the product is more
nucleophilic
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
than the reactant because alkyl groups are
activators for the Friedel–Crafts reaction. Consequently, overalkylation can occur.
Steric hindrance
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
can be exploited to limit the number of alkylations, as in the ''t''-butylation of 1,4-dimethoxybenzene.
:
Furthermore, the reaction is only useful for primary alkyl halides in an intramolecular sense when a 5- or 6-membered ring is formed. For the intermolecular case, the reaction is limited to
tertiary
Tertiary ( ) is a widely used but obsolete term for the geologic period from 66 million to 2.6 million years ago.
The period began with the demise of the non-avian dinosaurs in the Cretaceous–Paleogene extinction event, at the start ...
alkylating agents, some secondary alkylating agents (ones for which carbocation rearrangement is degenerate), or alkylating agents that yield stabilized carbocations (e.g., benzylic or allylic ones). In the case of primary alkyl halides, the carbocation-like complex (R
(+)---X---Al
(-)Cl
3) will undergo a
carbocation rearrangement reaction to give almost exclusively the rearranged product derived from a secondary or tertiary carbocation.
Mechanism
The general mechanism for primary alkyl halides is shown below.
:
For primary (and possibly secondary) alkyl halides, a carbocation-like complex with the Lewis acid,
(+)---(X---MX''n'')(–)">(+)---(X---MX''n'')(–)is more likely to be involved, rather than a free carbocation.
With Alkenes
In commercial applications, the alkylating agents are generally
alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s. Protonation of alkenes generates
carbocations, the electrophiles. A laboratory-scale example by the synthesis of
neophyl chloride from benzene and
methallyl chloride using sulfuric acid catalyst.
:
Such alkylations are of major industrial importance, e.g. for the production of
ethylbenzene, the precursor to polystyrene, from benzene and ethylene and for the production of cumene from benzene and propene in
cumene process:
:
:
Industrial production typically uses
solid acid
Solid is one of the four fundamental states of matter (the others being liquid, gas, and plasma). The molecules in a solid are closely packed together and contain the least amount of kinetic energy. A solid is characterized by structural ...
s derived from a
zeolite
Zeolites are microporous, crystalline aluminosilicate materials commonly used as commercial adsorbents and catalysts. They mainly consist of silicon, aluminium, oxygen, and have the general formula ・y where is either a metal ion or H+. These p ...
as the catalyst.
Friedel–Crafts dealkylation
Friedel–Crafts alkylations can be
reversible as illustrated by many
transalkylation
In organic chemistry, transalkylation is a chemical reaction involving the transfer of an alkyl group from one organic compound to another. The reaction is used for the transfer of methyl and ethyl groups between benzene rings. This is of particul ...
reactions.
[Tsai, Tseng-Chang "Disproportionation and Transalkylation of Alkylbenzenes over Zeolite Catalysts". Elsevier Science, 1999]
Acylation
Friedel–Crafts acylation involves the
acylation
In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent.
Because they form a strong electrophile when treated with ...
of aromatic rings. Typical acylating agents are
acyl chlorides.
Acid anhydride An acid anhydride is a type of chemical compound derived by the removal of water molecules from an acid.
In organic chemistry, organic acid anhydrides contain the functional group R(CO)O(CO)R'. Organic acid anhydrides often form when one equivale ...
s as well as carboxylic acids are also viable. A typical
Lewis acid catalyst is
aluminium trichloride. Because, however, the product ketone forms a rather stable complex with Lewis acids such as AlCl
3, a stoichiometric amount or more of the "catalyst" must generally be employed, unlike the case of the Friedel–Crafts alkylation, in which the catalyst is constantly regenerated. Reaction conditions are similar to the Friedel–Crafts alkylation. This reaction has several advantages over the alkylation reaction. Due to the electron-withdrawing effect of the
carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
group, the
ketone product is always less reactive than the original molecule, so multiple acylations do not occur. Also, there are no
carbocation rearrangements, as the
acylium ion is stabilized by a resonance structure in which the positive charge is on the oxygen.
:
The viability of the Friedel–Crafts acylation depends on the stability of the acyl chloride reagent. Formyl chloride, for example, is too unstable to be isolated. Thus, synthesis of
benzaldehyde through the Friedel–Crafts pathway requires that formyl chloride be synthesized ''in situ''. This is accomplished by the
Gattermann-Koch reaction, accomplished by treating benzene with
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
and
hydrogen chloride
The compound hydrogen chloride has the chemical formula and as such is a hydrogen halide. At room temperature, it is a colourless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapor. Hydrogen chloride ga ...
under high pressure, catalyzed by a mixture of
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
and
cuprous chloride. Simple ketones that could be obtained by Friedel–Crafts acylation are produced by alternative methods, e.g., oxidation, in industry.
Reaction mechanism
The reaction proceeds through generation of an acylium center. The reaction is completed by deprotonation of the
arenium ion by AlCl
4−, regenerating the AlCl
3 catalyst. However, in contrast to the truly catalytic alkylation reaction, the formed ketone is a moderate Lewis base, which forms a complex with the strong Lewis acid aluminum trichloride. The formation of this complex is typically irreversible under reaction conditions. Thus, a stochiometric quantity of AlCl
3 is needed. The complex is destroyed upon aqueous workup to give the desired ketone. For example, the classical synthesis of deoxybenzoin calls for 1.1 equivalents of AlCl
3 with respect to the limiting reagent, phenylacetyl chloride. In certain cases, generally when the benzene ring is activated, Friedel–Crafts acylation can also be carried out with ''catalytic'' amounts of a milder Lewis acid (e.g. Zn(II) salts) or a Brønsted acid catalyst using the anhydride or even the carboxylic acid itself as the acylation agent.
:
If desired, the resulting ketone can be subsequently reduced to the corresponding alkane substituent by either
Wolff–Kishner reduction
The Wolff–Kishner reduction is a reaction used in organic chemistry to convert carbonyl functionalities into methylene groups. In the context of complex molecule synthesis, it is most frequently employed to remove a carbonyl group after it has se ...
or
Clemmensen reduction
Clemmensen reduction is a chemical reaction described as a reduction of ketones (or aldehydes) to alkanes using zinc amalgam and concentrated hydrochloric acid. This reaction is named after Erik Christian Clemmensen, a Danish chemist.
The orig ...
. The net result is the same as the Friedel–Crafts alkylation except that rearrangement is not possible.
Hydroxyalkylation
Arenes react with certain
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
s and ketones to form the hydroxyalkylated products, for example in the reaction of the
mesityl derivative of
glyoxal
Glyoxal is an organic compound with the chemical formula OCHCHO. It is the smallest dialdehyde (a compound with two aldehyde groups). It is a crystalline solid, white at low temperatures and yellow near the melting point (15 °C). The liquid ...
with benzene:
:
As usual, the aldehyde group is more reactive electrophile than the
phenone.
Scope and variations
This reaction is related to several classic named reactions:
* The acylated reaction product can be converted into the alkylated product via a
Clemmensen and
Wolff-Kishner reductions.
* The
Gattermann–Koch reaction can be used to synthesize benzaldehyde from benzene.
* The
Gatterman reaction describes arene reactions with hydrocyanic acid.
* The
Houben–Hoesch reaction describes arene reactions with nitriles.
* A reaction modification with an aromatic phenyl ester as a reactant is called the
Fries rearrangement.
* In the
Scholl reaction
The Scholl reaction is a coupling reaction between two arene compounds with the aid of a Lewis acid and a protic acid.Grzybowski, M., Skonieczny, K., Butenschön, H. and Gryko, D. T. (2013), ''Comparison of Oxidative Aromatic Coupling and the Schol ...
two arenes couple directly (sometimes called Friedel–Crafts arylation).
* In the
Blanc chloromethylation a chloromethyl group is added to an arene with formaldehyde, hydrochloric acid and zinc chloride.
* The Bogert–Cook synthesis (1933) involves the
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
and
isomerization
In chemistry, isomerization or isomerisation is the process in which a molecule, polyatomic ion or molecular fragment is transformed into an isomer with a different chemical structure. Enolization is an example of isomerization, as is tautomeriz ...
of ''1-β-phenylethylcyclohexanol'' to the octahydro derivative of
phenanthrene
* The Darzens–Nenitzescu synthesis of ketones (1910, 1936) involves the acylation of
cyclohexene with
acetyl chloride
Acetyl chloride (CH3COCl) is an acyl chloride derived from acetic acid. It belongs to the class of organic compounds called acid halides. It is a colorless, corrosive, volatile liquid. Its formula is commonly abbreviated to AcCl.
Synthesis
On a ...
to methylcyclohexenylketone.
* In the related Nenitzescu reductive acylation (1936) a
saturated hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and hydrophobic, and their odors are usually weak or ...
is added making it a reductive acylation to methylcyclohexylketone
* The Nencki reaction (1881) is the ring acetylation of phenols with acids in the presence of zinc chloride.
* In a
green chemistry
Green chemistry, also called sustainable chemistry, is an area of chemistry and chemical engineering focused on the design of products and processes that minimize or eliminate the use and generation of hazardous substances. While environmental che ...
variation
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
is replaced by
graphite
Graphite () is a crystalline form of the element carbon. It consists of stacked layers of graphene. Graphite occurs naturally and is the most stable form of carbon under standard conditions. Synthetic and natural graphite are consumed on lar ...
in an alkylation of
''p''-xylene with
2-bromobutane. This variation will not work with primary halides from which less carbocation involvement is inferred.
Dyes
Friedel–Crafts reactions have been used in the synthesis of several
triarylmethane and
xanthene
Xanthene (9''H''-xanthene, 10''H''-9-oxaanthracene) is the organic compound with the formula CH2 6H4sub>2O. It is a yellow solid that is soluble in common organic solvents. Xanthene itself is an obscure compound, but many of its derivatives are us ...
dyes. Examples are the synthesis of
thymolphthalein (a pH indicator) from two equivalents of
thymol and
phthalic anhydride
Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used commer ...
:
:
A reaction of phthalic anhydride with
resorcinol
Resorcinol (or resorcin) is an organic compound with the formula C6H4(OH)2. It is one of three isomeric benzenediols, the 1,3-isomer (or '' meta''-isomer). Resorcinol crystallizes from benzene as colorless needles that are readily soluble i ...
in the presence of
zinc chloride
Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic and e ...
gives the fluorophore
fluorescein. Replacing resorcinol by N,N-diethylaminophenol in this reaction gives
rhodamine B:
:
Haworth reactions
The Haworth reaction is a classic method for the synthesis of
1-tetralone. In this reaction,
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms ...
is reacted with
succinic anhydride
Succinic anhydride, is an organic compound with the molecular formula (CH2CO)2O. This colorless solid is the acid anhydride of succinic acid.
Preparation
In the laboratory, this material can be prepared by dehydration of succinic acid. Such dehy ...
, the intermediate product is reduced and a second FC acylation takes place with addition of acid.
:
In a related reaction,
phenanthrene is synthesized from
naphthalene and succinic anhydride in a series of steps which begin with FC acylation.
:
Friedel–Crafts test for aromatic hydrocarbons
Reaction of
chloroform with aromatic compounds using an
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
catalyst gives triarylmethanes, which are often brightly colored, as is the case in triarylmethane dyes. This is a bench test for aromatic compounds.
[John C. Gilbert., Stephen F. Martin. Brooks/Cole CENGAGE Learning, 2011. pp 872. 25.10 Aromatic Hydrocarbons and Aryl Halides – Classification test. ]
See also
*
Ethylene oxide
Ethylene oxide is an organic compound with the formula . It is a cyclic ether and the simplest epoxide: a three-membered ring consisting of one oxygen atom and two carbon atoms. Ethylene oxide is a colorless and flammable gas with a faintly sw ...
*
Friedel family, a rich lineage of French scientists
*
Hydrodealkylation
*
Transalkylation
In organic chemistry, transalkylation is a chemical reaction involving the transfer of an alkyl group from one organic compound to another. The reaction is used for the transfer of methyl and ethyl groups between benzene rings. This is of particul ...
References
Friedel–Crafts reactions published on ''Organic Syntheses''
* Alkylations:
**
**
**
* Acylations:
**
**
**
**
**
**
**
{{DEFAULTSORT:Friedel-Crafts reaction
Substitution reactions
Carbon-carbon bond forming reactions
Name reactions