The Friedel–Crafts reactions are a set of
reactions developed by
Charles Friedel
Charles Friedel (; 12 March 1832 – 20 April 1899) was a French chemist and Mineralogy, mineralogist.
Life
A native of Strasbourg, France, he was a student of Louis Pasteur at the University of Paris, Sorbonne. In 1876, he became a professor of ...
and
James Crafts in 1877 to attach substituents to an
aromatic ring
In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
. Friedel–Crafts reactions are of two main types:
alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. 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 effecting al ...
reactions and
acylation
In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the foll ...
reactions. Both proceed by
electrophilic aromatic substitution
Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...
.
Alkylation
With alkenes
In commercial applications, the alkylating agents are generally
alkene
In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins.
The Internationa ...
s, some of the largest scale reactions practiced in industry.
Such alkylations are of major industrial importance, e.g. for the production of
ethylbenzene
Ethylbenzene is an organic compound with the formula . It is a highly flammable, colorless liquid with an odor similar to that of gasoline. This monocyclic aromatic hydrocarbon is important in the petrochemical industry as a reaction intermediat ...
, the precursor to polystyrene, from benzene and ethylene and for the production of cumene from benzene and propene in
cumene process
The cumene process (cumene-phenol process, Hock process) is an industrial process for synthesizing phenol and acetone from benzene and propylene. The term stems from cumene (isopropyl benzene), the intermediate material during the process. It ...
:
:
:
Industrial production typically uses
solid acid
Solid acids are acids that are insoluble in the reaction medium. They are often used as heterogeneous catalysts. Many solid acids are zeolites. A variety of techniques are used to quantify the strength of solid acids.
Examples
Examples of ino ...
s derived from a
zeolite
Zeolites are a group of several microporous, crystalline aluminosilicate minerals commonly used as commercial adsorbents and catalysts. They mainly consist of silicon, aluminium, oxygen, and have the general formula ・y where is either a meta ...
as the catalyst.
With alkyl halides
Friedel–Crafts alkylation involves the
alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. 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 effecting al ...
of an
aromatic ring
In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
. Traditionally, the alkylating agents are
alkyl halide
The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents of hydrogen atom. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalka ...
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, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...
s can be used in presence of protons. The reaction typically employs a strong
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
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
as catalyst, to increase the electrophilicity of the alkylating agent.
This reaction suffers from the disadvantage that the product is more
nucleophilic than the reactant because alkyl groups are
activators for the Friedel–Crafts reaction. Consequently, overalkylation can occur. However,
steric hindrance
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...
can be exploited to limit the number of successive alkylation cycles that occur, as in the ''t''-butylation of 1,4-dimethoxybenzene that gives only the product of two alkylation cycles and with only one of three possible isomers of it:
:
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 (from Latin, meaning 'third' or 'of the third degree/order..') may refer to:
* Tertiary period, an obsolete geologic period spanning from 66 to 2.6 million years ago
* Tertiary (chemistry), a term describing bonding patterns in organic ch ...
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
Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...
rearrangement reaction
In organic chemistry, a rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another at ...
to give almost exclusively the rearranged product derived from a secondary or tertiary carbocation.
Protonation of alkenes generates
carbocation
Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...
s, the electrophiles. A laboratory-scale example by the synthesis of
neophyl chloride from benzene and
methallyl chloride using
sulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...
catalyst.
:
Mechanism
The general mechanism for primary alkyl halides is shown in the figure 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.
Friedel–Crafts dealkylation
Friedel–Crafts alkylations can be
reversible. Although this is usually undesirable it can be exploited; for instance by facilitating
transalkylation reactions.
[Tsai, Tseng-Chang "Disproportionation and Transalkylation of Alkylbenzenes over Zeolite Catalysts". Elsevier Science, 1999]
It also allows alkyl chains to be added reversibly as
protecting group
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
In man ...
s. This approach is used industrially in the synthesis of
4,4'-biphenol via the oxidative coupling and subsequent dealkylation of
2,6-di-tert-butylphenol
2,6-Di-''tert''-butylphenol is an organic compound with the structural formula 2,6-((CH3)3C)2C6H3OH. This colorless solid alkylated phenol and its derivatives are used industrially as UV stabilizers and antioxidants for hydrocarbon-based produc ...
.
Acylation
Friedel–Crafts acylation involves the
acylation
In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the foll ...
of aromatic rings. Typical acylating agents are
acyl chloride
In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...
s.
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 . Organic acid anhydrides often form when one equivalent of wa ...
s as well as carboxylic acids are also viable. A typical
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 ...
catalyst is
aluminium trichloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
. 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 with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
group, the
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 ( ...
product is always less reactive than the original molecule, so multiple acylations do not occur. Also, there are no
carbocation
Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...
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
Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful.
It is a colorless liquid with a characteristic almond-li ...
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 poisonous, flammable gas that is colorless, odorless, tasteless, and slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the si ...
and
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 ...
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 a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
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
An arenium ion in organic chemistry is a cyclohexadienyl cation that appears as a reactive intermediate in electrophilic aromatic substitution.
For historic reasons this complex is also called a Wheland intermediate, after American chemist George ...
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 or
Clemmensen reduction
Clemmensen reduction is a chemical reaction described as a Redox, reduction of ketones or aldehydes to alkanes using zinc Amalgam (chemistry), amalgam and concentrated hydrochloric acid (HCl). This reaction is named after Erik Christian Clemmensen ...
. 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 () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
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 or a
Wolff-Kishner reduction.
* The
Gattermann–Koch reaction can be used to synthesize benzaldehyde from benzene.
* The
Gatterman reaction
The Gattermann reaction (also known as the Gattermann formylation and the Gattermann salicylaldehyde synthesis) is a chemical reaction in which aromatic compounds are formylation reaction, formylated by a mixture of hydrogen cyanide (HCN) and hy ...
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
The Fries rearrangement, named for the German chemist Karl Theophil Fries, is a rearrangement reaction of a phenolic ester to a Hydroxyl, hydroxy aryl ketone by catalysis of Lewis acids.
It involves migration of an acyl group of phenol ester to t ...
.
* In the
Scholl reaction two arenes couple directly (sometimes called Friedel–Crafts arylation).
* In the
Blanc chloromethylation
The Blanc chloromethylation (also called the Blanc reaction) is the chemical reaction of aromatic rings with formaldehyde and hydrogen chloride to form chloromethyl arenes. The reaction is catalyzed by Lewis acids such as zinc chloride. The reac ...
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 that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
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 tautomer ...
of ''1-β-phenylethylcyclohexanol'' to the octahydro derivative of
phenanthrene
Phenanthrene is a polycyclic aromatic hydrocarbon (PAH) with formula C14H10, consisting of three fused benzene rings. It is a colorless, crystal-like solid, but can also appear yellow. Phenanthrene is used to make dyes, plastics, pesticides, expl ...
* The Darzens–Nenitzescu synthesis of ketones (1910, 1936) involves the acylation of
cyclohexene
Cyclohexene is a hydrocarbon with the formula . It is a cycloalkene. At room temperature, cyclohexene is a colorless liquid with a sharp odor. Among its uses, it is an chemical intermediate, intermediate in the commercial synthesis of nylon.
Prod ...
with
acetyl chloride
Acetyl chloride () 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 an ...
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 Hydrophobe, hydrophobic; their odor is usually fain ...
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, similar to sustainable chemistry or circular 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. Wh ...
variation
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
is replaced by
graphite
Graphite () is a Crystallinity, crystalline allotrope (form) of the element carbon. It consists of many stacked Layered materials, layers of graphene, typically in excess of hundreds of layers. Graphite occurs naturally and is the most stable ...
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 u ...
dye
Juan de Guillebon, better known by his stage name DyE, is a French musician. He is known for the music video of the single "Fantasy
Fantasy is a genre of speculative fiction that involves supernatural or Magic (supernatural), magical ele ...
s. Examples are the synthesis of
thymolphthalein (a pH indicator) from two equivalents of
thymol
Thymol (also known as 2-isopropyl-5-methylphenol, IPMP), , is a toxic monoterpenoid phenol derivative of ''p''-Cymene, isomeric with carvacrol. It occurs naturally in the oil of thyme, and it is extracted from ''Thymus vulgaris'' (common thy ...
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 a phenolic compound. It is an organic compound with the formula C6H4(OH)2. It is one of three isomeric benzenediols, the 1,3-isomer (or ''meta- (chemistry), meta''-isomer). Resorcinol crystallizes from benzene as co ...
in the presence of
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 ...
gives the fluorophore
fluorescein
Fluorescein is an organic compound and dye based on the xanthene tricyclic structural motif, formally belonging to Triarylmethane dye, triarylmethine dyes family. It is available as a dark orange/red powder slightly soluble in water and alcohol. ...
. Replacing resorcinol by N,N-diethylaminophenol in this reaction gives
rhodamine B:
:
Haworth synthesis
The
Haworth synthesis is a classic method for the synthesis of polycyclic aromatic hydrocarbons. In this reaction, an
arene
Aromatic compounds or arenes are organic compounds "with a chemistry typified by benzene" and "cyclically conjugated."
The word "aromatic" originates from the past grouping of molecules based on odor, before their general chemical properties were ...
is reacted with
succinic anhydride, the subsequent product is then reduced in either a
Clemmensen reduction
Clemmensen reduction is a chemical reaction described as a Redox, reduction of ketones or aldehydes to alkanes using zinc Amalgam (chemistry), amalgam and concentrated hydrochloric acid (HCl). This reaction is named after Erik Christian Clemmensen ...
or a
Wolff-Kishner reduction. Lastly, a second Friedel-Crafts acylation takes place with addition of acid.
:
The product formed in this reaction is then analogously reduced, followed by a dehydrogenation reaction (with the reagent
SeO2 for example) to extend the aromatic ring system.
Friedel–Crafts test for aromatic hydrocarbons
Reaction of
chloroform
Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...
with aromatic compounds using an
aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
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
*
Friedel family, lineage of French scientists
*
Hydrodealkylation
*
Transalkylation
References
Friedel–Crafts reactions published on ''Organic Syntheses''
* Alkylations:
**
**
**
* Acylations:
**
**
**
**
**
**
**
{{DEFAULTSORT:Friedel-Crafts reaction
Substitution reactions
Carbon-carbon bond forming reactions
Name reactions