Friedel–Crafts reaction

Friedel-Crafts acylation
Named after	Charles Friedel ; James Crafts
Reaction type	Coupling reaction
Reaction
	Aromatic Ring
	+; Acylating agents
	↓
	Friedel-Crafts aromatic addition product
	+; HCl (reaction type dependent)
Conditions
Catalyst	Strong lewis acid: ; Zeolite, AlCl3
Identifiers
Organic Chemistry Portal	friedel-crafts-acylation
RSC ontology ID	RXNO:0000045

Friedel-Crafts alkylation
Named after	Charles Friedel ; James Crafts
Reaction type	Coupling reaction
Reaction
	Aromatic Ring
	+; Alkylating Agent
	↓
	Friedel-Crafts aromatic addition product
	+; HCl (reaction type dependent)
Conditions
Catalyst	Strong lewis acid: ; Zeolite, AlCl3
Identifiers
Organic Chemistry Portal	friedel-crafts-alkylation
RSC ontology ID	RXNO:0000046

Friedel-Crafts reaction
Named after	Charles Friedel ; James Crafts
Reaction type	Coupling reaction
Reaction
	Aromatic Ring
	+; Alkyl Halide, Alcohol, Alkene or Alkyne
	↓
	Coupling Product
Conditions
Catalyst	Strong lewis acid: ; Zeolite, AlCl3
Identifiers
RSC ontology ID	RXNO:0000369

Last updated February 15, 2024

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.^[1] Friedel–Crafts reactions are of two main types: alkylation reactions and acylation reactions. Both proceed by electrophilic aromatic substitution.^[2]^[3]^[4]^[5]

Alkylation

With alkenes

In commercial applications, the alkylating agents are generally alkenes, some of the largest scale reactions practiced in industry. 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 acids derived from a zeolite as the catalyst.

With alkyl halides

Friedel–Crafts alkylation involves the alkylation of an aromatic ring. Traditionally, the alkylating agents are alkyl halides. Many alkylating agents can be used instead of alkyl halides. For example, enones and epoxides can be used in presence of protons. Traditionally also, the reaction employs a strong Lewis acid, such as aluminium chloride as catalyst.^[6]

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. Steric hindrance can be exploited to limit the number of alkylations, as in the t-butylation of 1,4-dimethoxybenzene.^[7]

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 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^(-)Cl₃) will undergo a carbocation rearrangement reaction to give almost exclusively the rearranged product derived from a secondary or tertiary carbocation.^[8]

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.^[9]

Mechanism

The general mechanism for primary alkyl halides is shown below.^[8]

For primary (and possibly secondary) alkyl halides, a carbocation-like complex with the Lewis acid, [R⁽⁺⁾---(X---MX_n)^(–)] is more likely to be involved, rather than a free carbocation.

Friedel–Crafts dealkylation

Friedel–Crafts alkylations can be reversible as illustrated by many transalkylation reactions.^[10]

Acylation

Friedel–Crafts acylation involves the acylation of aromatic rings. Typical acylating agents are acyl chlorides. Acid anhydrides 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 AlCl₃, 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.^[11] 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 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 and hydrogen chloride under high pressure, catalyzed by a mixture of aluminium chloride 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 AlCl₄⁻, regenerating the AlCl₃ 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 AlCl₃ 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 AlCl₃ with respect to the limiting reagent, phenylacetyl chloride.^[12] 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. The net result is the same as the Friedel–Crafts alkylation except that rearrangement is not possible.^[13]

Hydroxyalkylation

Arenes react with certain aldehydes and ketones to form the hydroxyalkylated products, for example in the reaction of the mesityl derivative of glyoxal with benzene:^[14]

As usual, the aldehyde group is more reactive electrophile than the phenone.

Scope and variations

Alkylation of benzene & ethylene, one of the largest scale reactions practiced commercially. EthylbenzenePost2000route.svg — Alkylation of benzene & ethylene, one of the largest scale reactions practiced commercially.

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.^[15]
The Gattermann–Koch reaction can be used to synthesize benzaldehyde from benzene.^[16]
The Gatterman reaction describes arene reactions with hydrocyanic acid.^[17]^[18]
The Houben–Hoesch reaction describes arene reactions with nitriles.^[19]
A reaction modification with an aromatic phenyl ester as a reactant is called the Fries rearrangement.
In the Scholl reaction two arenes couple directly (sometimes called Friedel–Crafts arylation).^[20]
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 and isomerization of 1-β-phenylethylcyclohexanol to the octahydro derivative of phenanthrene ^[21]

The Darzens–Nenitzescu synthesis of ketones (1910, 1936) involves the acylation of cyclohexene with acetyl chloride to methylcyclohexenylketone.
In the related Nenitzescu reductive acylation (1936) a saturated hydrocarbon 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.^[22]
In a green chemistry variation aluminium chloride is replaced by graphite in an alkylation of p-xylene with 2-bromobutane. This variation will not work with primary halides from which less carbocation involvement is inferred.^[23]

Dyes

Friedel–Crafts reactions have been used in the synthesis of several triarylmethane and xanthene dyes.^[24] Examples are the synthesis of thymolphthalein (a pH indicator) from two equivalents of thymol and phthalic anhydride:

A reaction of phthalic anhydride with resorcinol in the presence of zinc chloride 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.^[25] In this reaction, benzene is reacted with succinic anhydride, the intermediate product is reduced and a second FC acylation takes place with addition of acid.^[26]

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 catalyst gives triarylmethanes, which are often brightly colored, as is the case in triarylmethane dyes. This is a bench test for aromatic compounds.^[27]

Related Research Articles

In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited to a fragment that departs with a pair of electrons in heterolytic bond cleavage. In this usage, a leaving group is a less formal but more commonly used synonym of the term nucleofuge. In this context, leaving groups are generally anions or neutral species, departing from neutral or cationic substrates, respectively, though in rare cases, cations leaving from a dicationic substrate are also known.

<span class="mw-page-title-main">Alkylation</span> Transfer of an alkyl group from one molecule to another

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. Alkylating agents are reagents for effecting alkylation. Alkyl groups can also be removed in a process known as dealkylation. Alkylating agents are often classified according to their nucleophilic or electrophilic character. In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. For upgrading of petroleum, alkylation produces a premium blending stock for gasoline. In medicine, alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents.

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 following:

<span class="mw-page-title-main">Acyl halide</span> Oxoacid compound with an –OH group replaced by a halogen

In organic chemistry, an acyl halide is a chemical compound derived from an oxoacid by replacing a hydroxyl group with a halide group.

<span class="mw-page-title-main">Aluminium chloride</span> Chemical compound

Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula AlCl₃. It forms a hexahydrate with the formula [Al(H₂O)₆]Cl₃, containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are colourless crystals, but samples are often contaminated with iron(III) chloride, giving them a yellow colour.

The Pummerer rearrangement is an organic reaction whereby an alkyl sulfoxide rearranges to an α-acyloxy–thioether (monothioacetal-ester) in the presence of acetic anhydride.

Gold(III) chloride, traditionally called auric chloride, is an inorganic compound of gold and chlorine with the molecular formula Au₂Cl₆. The "III" in the name indicates that the gold has an oxidation state of +3, typical for many gold compounds. It has two forms, the monohydrate (AuCl₃·H₂O) and the anhydrous form, which are both hygroscopic and light-sensitive solids. This compound is a dimer of AuCl₃. This compound has a few uses, such as an oxidizing agent and for catalyzing various organic reactions.

Clemmensen reduction is a chemical reaction described as a reduction of ketones or aldehydes to alkanes using zinc amalgam and concentrated hydrochloric acid (HCl). This reaction is named after Erik Christian Clemmensen, a Danish-American chemist.

The Fries rearrangement, named for the German chemist Karl Theophil Fries, is a rearrangement reaction of a phenolic ester to a hydroxy aryl ketone by catalysis of Lewis acids.

A carbenium ion is a positive ion with the structure RR′R″C⁺, that is, a chemical species with carbon atom having three covalent bonds, and it bears a +1 formal charge. But IUPAC confuses coordination number with valence, incorrectly considering carbon in carbenium as trivalent.

The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor or another electrophilic alkylation reagent to give an alkylated iminium product, which is hydrolyzed by dilute aqueous acid to give the alkylated ketone or aldehyde. Since enamines are generally produced from ketones or aldehydes, this overall process constitutes a selective monoalkylation of a ketone or aldehyde, a process that may be difficult to achieve directly.

Lanthanide triflates are triflate salts of the lanthanides. These salts have been investigated for application in organic synthesis as Lewis acid catalysts. These catalysts function similarly to aluminium chloride or ferric chloride, but they are water-tolerant (stable in water). Commonly written as Ln(OTf)₃·(H₂O)₉ the nine waters are bound to the lanthanide, and the triflates are counteranions, so more accurately lanthanide triflate nonahydrate is written as [Ln(H₂O)₉](OTf)₃.

<span class="mw-page-title-main">Tetrachloroaluminate</span> Ion

Tetrachloroaluminate [AlCl₄]⁻ is an anion formed from aluminium and chlorine. The anion has a tetrahedral shape, similar to carbon tetrachloride where carbon is replaced with aluminium. Some tetrachloroaluminates are soluble in organic solvents, creating an ionic non-aqueous solution, making them suitable as component of electrolytes for batteries. For example, lithium tetrachloroaluminate is used in some lithium batteries.

Organomanganese chemistry is the chemistry of organometallic compounds containing a carbon to manganese chemical bond. In a 2009 review, Cahiez et al. argued that as manganese is cheap and benign, organomanganese compounds have potential as chemical reagents, although currently they are not widely used as such despite extensive research.

The Minisci reaction is a named reaction in organic chemistry. It is a nucleophilic radical substitution to an electron deficient aromatic compound, most commonly the introduction of an alkyl group to a nitrogen containing heterocycle. The reaction was published in 1971 by F. Minisci. In the case of N-Heterocycles, the conditions must be acidic to ensure protonation of said heterocycle. A typical reaction is that between pyridine and pivalic acid with silver nitrate, sulfuric acid and ammonium persulfate to form 2-tert-butylpyridine. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.

Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic nitration, aromatic halogenation, aromatic sulfonation, alkylation and acylation Friedel–Crafts reaction.

In Lewis acid catalysis of organic reactions, a metal-based Lewis acid acts as an electron pair acceptor to increase the reactivity of a substrate. Common Lewis acid catalysts are based on main group metals such as aluminum, boron, silicon, and tin, as well as many early and late d-block metals. The metal atom forms an adduct with a lone-pair bearing electronegative atom in the substrate, such as oxygen, nitrogen, sulfur, and halogens. The complexation has partial charge-transfer character and makes the lone-pair donor effectively more electronegative, activating the substrate toward nucleophilic attack, heterolytic bond cleavage, or cycloaddition with 1,3-dienes and 1,3-dipoles.

Imidoyl chlorides are organic compounds that contain the functional group RC(NR')Cl. A double bond exist between the R'N and the carbon centre. These compounds are analogues of acyl chloride. Imidoyl chlorides tend to be highly reactive and are more commonly found as intermediates in a wide variety of synthetic procedures. Such procedures include Gattermann aldehyde synthesis, Houben-Hoesch ketone synthesis, and the Beckmann rearrangement. Their chemistry is related to that of enamines and their tautomers when the α hydrogen is next to the C=N bond. Many chlorinated N-heterocycles are formally imidoyl chlorides, e.g. 2-chloropyridine, 2, 4, and 6-chloropyrimidines.

<span class="mw-page-title-main">1-Tetralone</span> Chemical compound

1-Tetralone is a bicyclic aromatic hydrocarbon and a ketone. In terms of its structure, it can also be regarded as benzo-fused cyclohexanone. It is a colorless oil with a faint odor. It is used as starting material for agricultural and pharmaceutical agents. The carbon skeleton of 1-tetralone is found in natural products such as Aristelegone A (4,7-dimethyl-6-methoxy-1-tetralone) from the family of Aristolochiaceae used in traditional Chinese medicine.

Hafnium(IV) triflate or hafnium trifluoromethansulfonate is a salt with the formula Hf(OSO₂CF₃)₄, also written as Hf(OTf)₄. Hafnium triflate is used as an impure mixture as a catalyst. Hafnium (IV) has an ionic radius of intermediate range (Al < Ti < Hf < Zr < Sc < Ln) and has an oxophilic hard character typical of group IV metals. This solid is a stronger Lewis acid than its typical precursor hafnium tetrachloride, HfCl₄, because of the strong electron-withdrawing nature of the four triflate groups, which makes it a great Lewis acid and has many uses including as a great catalyst at low Lewis acid loadings for electrophilic aromatic substitution and nucleophilic substitution reactions.

References

↑ Friedel, C.; Crafts, J. M. (1877) "Sur une nouvelle méthode générale de synthèse d'hydrocarbures, d'acétones, etc.," Compt. Rend., 84: 1392 & 1450.
↑ Price, C. C. (1946). "The Alkylation of Aromatic Compounds by the Friedel-Crafts Method". Org. React. 3: 1. doi:10.1002/0471264180.or003.01. ISBN 0471264180.
↑ Groves, J. K. (1972). "The Friedel–Crafts acylation of alkenes". Chem. Soc. Rev. 1: 73. doi:10.1039/cs9720100073.
↑ Eyley, S. C. (1991). "The Aliphatic Friedel–Crafts Reaction". Compr. Org. Synth. 2: 707–731. doi:10.1016/B978-0-08-052349-1.00045-7. ISBN 978-0-08-052349-1.
↑ Heaney, H. (1991). "The Bimolecular Aromatic Friedel–Crafts Reaction". Compr. Org. Synth. 2: 733–752. doi:10.1016/B978-0-08-052349-1.00046-9. ISBN 978-0-08-052349-1.
↑ Rueping, M.; Nachtsheim, B. J. (2010). "A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis". Beilstein J. Org. Chem. 6 (6): 6. doi:10.3762/bjoc.6.6. PMC 2870981 . PMID 20485588.
↑ L., Williamson, Kenneth (4 January 2016). Macroscale and microscale organic experiments. Masters, Katherine M. (Seventh ed.). Boston, MA, USA. ISBN 9781305577190. OCLC 915490547.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: multiple names: authors list (link)
1 2 Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN 978-0-471-72091-1
↑ Smith, W. T. Jr.; Sellas, J. T. (1952). "Neophyl Chloride". Organic Syntheses . 32: 90. doi:10.15227/orgsyn.032.0090.
↑ Tsai, Tseng-Chang "Disproportionation and Transalkylation of Alkylbenzenes over Zeolite Catalysts". Elsevier Science, 1999
↑ Somerville, L. F.; Allen, C. F. H. (1933). "β-Benzoylpropionic acid". Organic Syntheses. 13: 12. doi:10.15227/orgsyn.013.0012.
↑ "Desoxybenzoin". orgsyn.org. Retrieved 26 January 2019.
↑ Friedel-Crafts Acylation. Organic-chemistry.org. Retrieved 2014-01-11.
↑ Fuson, R. C.; Weinstock, H. H.; Ullyot, G. E. (1935). "A New Synthesis of Benzoins. 2′,4′,6′-Trimethylbenzoin". J. Am. Chem. Soc. 57 (10): 1803–1804. doi:10.1021/ja01313a015.
↑ Smith & March 2001, p. 1835.
↑ Smith & March 2001, p. 745.
↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, p. 725, ISBN 978-0-471-72091-1
↑ Smith, M.B.; March, J (2001). March's Advanced Organic Chemistry. p. 725. ISBN 0-471-58589-0.
↑ Smith & March 2001, p. 732.
↑ Grzybowski, M.; Skonieczny, K.; Butenschön, H.; Gryko, D. T. (2013). "Comparison of Oxidative Aromatic Coupling and the Scholl Reaction". Angew. Chem. Int. Ed. 52 (38): 9900–9930. doi:10.1002/anie.201210238. PMID 23852649.
↑ This reaction with phosphorus pentoxide: Kamp, J. V. D.; Mosettig, E. (1936). "Trans- and Cis-As-Octahydrophenanthrene". Journal of the American Chemical Society. 58 (6): 1062–1063. doi:10.1021/ja01297a514.
↑ Nencki, M.; Sieber, N. (1881). "Ueber die Verbindungen der ein- und zweibasischen Fettsäuren mit Phenolen". J. Prakt. Chem. (in German). 23: 147–156. doi:10.1002/prac.18810230111.
↑ Sereda, Grigoriy A.; Rajpara, Vikul B. (2007). "A Green Alternative to Aluminum Chloride Alkylation of Xylene". J. Chem. Educ. 2007 (84): 692. Bibcode:2007JChEd..84..692S. doi:10.1021/ed084p692.
↑ McCullagh, James V.; Daggett, Kelly A. (2007). "Synthesis of Triarylmethane and Xanthene Dyes Using Electrophilic Aromatic Substitution Reactions". J. Chem. Educ. 84 (11): 1799. Bibcode:2007JChEd..84.1799M. doi:10.1021/ed084p1799.
↑ Haworth, Robert Downs (1932). "Syntheses of alkylphenanthrenes. Part I. 1-, 2-, 3-, and 4-Methylphenanthrenes". J. Chem. Soc. : 1125. doi:10.1039/JR9320001125.
↑ Li, Jie Jack (2003) Name Reactions: A Collection of Detailed Reaction Mechanisms, Springer, ISBN 3-540-40203-9, p. 175.
↑ John C. Gilbert., Stephen F. Martin. Brooks/Cole CENGAGE Learning, 2011. pp 872. 25.10 Aromatic Hydrocarbons and Aryl Halides – Classification test. ISBN 978-1-4390-4914-3