Friedel-Crafts reaction
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The '''Friedel-Crafts reactions''' are a set of [[organic reaction|reactions]] developed by [[Charles Friedel]] and [[James Crafts]] in [[1877]].<ref>Friedel, C.; Crafts, J. M. ''Compt. Rend.'' '''1877''', ''84'', [http://gallica.bnf.fr/ark:/12148/bpt6k30410/f1386.table 1392] & [http://gallica.bnf.fr/ark:/12148/bpt6k30410/f1444.table 1450].</ref> There are two main types of Friedel-Crafts reactions: [[alkylation]] reactions and [[acylation]] reactions. This reaction type is part of [[electrophilic aromatic substitution]].
[[Image:Friedel-craft-alk2.gif|500px|center|The Friedel-Crafts alkylation of benzene with methyl chloride]]
Several reviews have been written.<ref>Price, C. C. ''Org. React.'' '''1946''', ''3'', 1. (Review)</ref><ref>Groves, J. K. ''[[Chem. Soc. Rev.]]'' '''1972''', ''1'', 73. (Review)</ref><ref>Eyley, S. C. ''Comp. Org. Syn.'' '''1991''', ''2'', 707-731. (Review)</ref><ref>Heaney, H. ''Comp. Org. Syn.'' '''1991''', ''2'', 733-752. (Review)</ref>
== Friedel-Crafts alkylation ==<!-- This section is linked from [[Cumene process]] -->
Friedel-Crafts alkylation involves the alkylation of an [[aromatic ring]] and an [[alkyl halide]] using a strong [[Lewis acid]] catalyst. With anhydrous [[ferric chloride]] as a [[catalyst]], the alkyl group attaches at the former site of the chloride ion.
[[Image:Friedel Crafts mechanism.png|500px|center|Mechanism for the Friedel Crafts alkylation]]
This reaction has one big disadvantage, namely that the product is more [[nucleophile|nucleophilic]] than the reactant due to the electron donating alkyl-chain. Therefore, another hydrogen is substituted with an alkyl-chain, which leads to overalkylation of the molecule. Also, if the chlorine is not on a [[tertiary carbon]], [[carbocation]] [[rearrangement reaction]] will occur. This is due to the relative stability of the tertiary [[carbocation]] over the secondary and primary carbocations.
[[Steric hindrance]] can be exploited to limit the number of alkylations, as in the t-butylation of 1,4-dimethoxybenzene.
[[Image:Friedel-CraftsAlkylationStericProtection.png|center|350px|t-butylation of 1,4-dimethoxybenzene]]
Alkylations are not limited to alkyl halides: Friedel-Crafts reactions are possible with any [[carbocation]]ic intermediate such as those derived from [[alkene]]s and a [[protic acid]] or [[lewis acid]], [[enone]]s and [[epoxide]]s. In one study the electrophile is a [[bromonium ion]] derived from an alkene and [[N-Bromosuccinimide|NBS]]:<ref>{{cite journal | author = S. Hajra, B. Maji and S. Bar | title = Samarium Triflate-Catalyzed Halogen-Promoted Friedel-Crafts Alkylation with Alkenes | year = 2007 | journal = [[Org. Lett.]] | volume = 9 | issue = 15 | pages = 2783–2786 | doi = 10.1021/ol070813t}}</ref>
[[Image:FriedelCraftsAlkylationAlkenes.png|400px|center|Friedel-Crafts alkylation by an alkene]]
In this reaction [[samarium(III) triflate]] is believed to activate the NBS halogen donor in halonium ion formation.
==Friedel-Crafts dealkylation==
Friedel-Crafts alkylation is a [[reversible reaction]]. In a '''reversed Friedel-Crafts reaction''' or '''Friedel-Crafts dealkylation''', alkyl groups can be removed in the presence of protons and a [[Lewis acid]].
For example, in a multiple addition of [[bromoethane|ethyl bromide]] to [[benzene]], [[Arene substitution patterns|''ortho'' and ''para'' substitution]] is expected after the first monosubstitution step because an alkyl group is an [[activating group]]. However, the actual reaction product is 1,3,5-triethylbenzene with all alkyl groups as a [[aromatic meta substituent|meta substituent]].<ref>{{cite journal | author = K. Wallace, R. Hanes, E. Anslyn, J. Morey, K. Kilway and J. Siegel | title = Preparation of 1,3,5-Tris(aminomethyl)-2,4,6-triethylbenzene from Two Versatile 1,3,5-Tri(halosubstituted) 2,4,6-Triethylbenzene Derivatives | year = 2005 | journal = [[Synthesis (journal)|Synthesis]] | volume = 2005| issue = 12 | pages = 2080–2083 | doi = 10.1055/s-2005-869963}}</ref> [[Thermodynamic reaction control]] makes sure that thermodynamically favored ''meta'' substitution with [[steric hindrance]] minimized takes prevalence over less favorable ''ortho'' and ''para'' substitution by [[chemical equilibrium|chemical equilibration]]. The ultimate reaction product is thus the result of a series of alkylations and dealkylations.
[[Image:246triethylbenzene.png|center|300px|synthesis of 2,4,6-triethylbenzene]]
== Friedel-Crafts acylation ==
Friedel-Crafts acylation is the [[acylation]] of aromatic rings with an [[acyl chloride]] using a strong [[Lewis acid]] catalyst. Friedel-Crafts acylation is also possible with [[acid anhydride]]s. Reaction conditions are similar to the Friedel-Crafts alkylation mentioned above. 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 carbonium ion is stabilized by a resonance structure in which the positive charge is on the oxygen.
[[Image:Friedel-Crafts-acylation-overview.png|350px|center|Friedel-Crafts acylation overview]]
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]] via the Friedel-Crafts pathway requires that formyl chloride be synthesized ''in situ''. This is accomplished via the [[Gatterman-Koch reaction|Gatterman-Koch Synthesis]], accomplished by reacting [[benzene]] with [[carbon monoxide]] and [[hydrogen chloride]] under high pressure, catalyzed by a mixture of [[aluminium chloride]] and [[cuprous chloride]].
=== Reaction mechanism ===
In a simple mechanistic view, the first step consists of dissociation of a chlorine atom to form an [[acyl]] cation:
:[[Image:Friedel-Crafts-acylation-step-1.png|250px|FC acylation step 1]]
This is followed by nucleophilic attack of the arene toward the acyl group:
:[[Image:Friedel-Crafts-acylation-step-2.png|200px|FC acylation step II]]
Finally, a chlorine atom reacts to form HCl, and the AlCl<sub>3</sub> catalyst is regenerated:
:[[Image:Friedel-Crafts-acylation-step-3.png|300px|FC acylation step III]]
==Friedel-Crafts hydroxyalkylation==
Arenes react with certain [[aldehyde]]s and [[ketone]]s to the hydroxyalkylated product for example in the reaction of the [[mesityl]] derivative of [[glyoxal]] with benzene<ref>{{cite journal | author = R. C. Fuson, H. H. Weinstock and G. E. Ullyot | title = A New Synthesis of Benzoins. 2′,4′,6′-Trimethylbenzoin | year = 1935 | journal = [[J. Am. Chem. Soc.]] | volume = 57 | issue = 10 | pages = 1803–1804 | doi = 10.1021/ja01313a015}}</ref> to form a [[benzoin]] with an [[alcohol]] rather than a [[carbonyl]] group:
[[Image:FriedelCraftsHydroAlkylation.png|400px|center|Friedel-Crafts hydroxyalkylaiton]]
==Scope & variations==
This reaction is related to several classic named reactions:
* The acylated reaction product can be converted into the alkylated product via a [[Clemmensen reduction]].
* 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]] two arenes couple directly (sometimes called '''Friedel-Crafts arylation''').
* In the [[Zincke-Suhl reaction]] p-cresol is alkylated to a cyclohexadienone with tetrachloromethane
* 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]] <ref>This reaction with
[[phosphorus pentoxide]]: {{cite journal | author = J. v. d. Kamp and E. Mosettig | title = Trans- And Cis-As-Octahydrophenanthrene | year = 1936 | journal = [[J. Am. Chem. Soc.]] | volume = 58 | issue = 6 | pages = 1062–1063 | doi = 10.1021/ja01297a514 }}</ref>
* The '''Darzens-Nenitzescu Synthesis of Ketones''' (1910, 1936) <ref>[http://www.drugfuture.com/OrganicNameReactions/onr94.htm Darzens-Nenitzescu Synthesis of Ketones<!-- Bot generated title -->]</ref> involves the acylation of [[cyclohexene]] with [[acetyl chloride]] to methylcyclohexenylketone.
* In the related '''Nenitzescu reductive acylation''' (1936) <ref>[http://www.drugfuture.com/OrganicNameReactions/onr277.htm Nenitzescu Reductive Acylation<!-- Bot generated title -->]</ref> a [[saturated]] [[hydrocarbon]] is added making it a reductive acylation to methylcyclohexylketone
* 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.<ref>{{cite journal | title = A Green Alternative to Aluminum Chloride Alkylation of Xylene | author = Sereda, Grigoriy A.; Rajpara, Vikul B. | journal = [[J. Chem. Educ.]] | year = 2007 | volume = 2007 | issue = 84 | pages = 692 | url = http://jchemed.chem.wisc.edu/Journal/Issues/2007/Apr/abs692.html}}</ref>
===Dyes===
Friedel-Crafts reactions have been used in the synthesis of several [[Triphenylmethane|triarylmethane]] and [[xanthene]] [[dye]]s <ref>''Synthesis of Triarylmethane and Xanthene Dyes Using Electrophilic Aromatic Substitution Reactions'' James V. McCullagh and Kelly A. Daggett [[J. Chem. Educ.]] '''2007''', 84, 1799. [http://jchemed.chem.wisc.edu/Journal/Issues/2007/Nov/abs1799.html Abstract]</ref>. Examples are the synthesis of [[thymolphthalein]] (a pH indicator) from two equivalents of [[thymol]] and [[phthalic anhydride]]:
:[[Image:ThymolphthaleinSynthesis.png|400px|Thymolphthalein Synthesis]]
A reaction of phthalic anhydride with [[resorcinol]] in the presence of [[zinc chloride]] gives the fluorophore [[Fluorescein#Synthesis|Fluorescein]]. Replacing resorcinol by N,N-diethylaminophenol in this reaction gives [[rhodamine B]]:
:[[Image:RhodamineBsynthesis.png|400px|Rhodamine B synthesis]]
== References ==
{{reflist}}
===FC reactions in Org. Synth.===
Friedel-Crafts reactions appear in [[Organic Syntheses]]:
* Alkylations:
** Diphenylacetone, Organic Syntheses, Coll. Vol. 3, p.343 (1955); Vol. 29, p.38 (1949) [http://orgsynth.org/orgsyn/pdfs/CV3P0343.pdf Article link].
** Reaction of [[p-xylene]] with [[chloromethane]] to [[durene]] Organic Syntheses, Coll. Vol. 2, p.248 (1943); Vol. 10, p.32 (1930). [http://orgsynth.org/orgsyn/pdfs/CV2P0248.pdf Article link]
** Synthesis of [[benzophenone]] from [[benzene]] and [[tetrachloromethane]] Organic Syntheses, Coll. Vol. 1, p.95 (1941); Vol. 8, p.26 (1928).[http://orgsynth.org/orgsyn/pdfs/CV1P0095.pdf Article link]
* Acylations:
** Dibenzoylethylene Organic Syntheses, Coll. Vol. 3, p.248 (1955); Vol. 20, p.29 (1940) [http://orgsynth.org/orgsyn/pdfs/CV3P0248.pdf Article link].
** reaction of [[acenaphthene]] plus [[succinic acid]] Organic Syntheses, Coll. Vol. 3, p.6 (1955); Vol. 20, p.1 (1940).[http://orgsynth.org/orgsyn/pdfs/CV3P0006.pdf Article link]
** Desoxybenzoin Organic Syntheses, Coll. Vol. 2, p.156 (1943); Vol. 12, p.16 (1932). [http://orgsynth.org/orgsyn/pdfs/CV2P0156.pdf Article link]
** Acylation of a [[phenanthrene]] compound Organic Syntheses, Vol. 80, p.227 [http://orgsynth.org/orgsyn/pdfs/v80p0227.pdf Link]
** Reaction of [[bromobenzene]] with [[acetic anhydride]] Organic Syntheses, Coll. Vol. 1, p.109 (1941); Vol. 5, p.17 (1925). [http://orgsynth.org/orgsyn/pdfs/CV1P0109.pdf Article link]
** beta-methylanthraquinone, Organic Syntheses, Coll. Vol. 1, p.353 (1941); Vol. 4, p.43 (1925). [http://orgsynth.org/orgsyn/pdfs/CV1P0353.pdf Article link]
** Benzoylation of [[ferrocene]] Organic Syntheses, Coll. Vol. 6, p.625 (1988); Vol. 56, p.28 (1977). [http://orgsynth.org/orgsyn/pdfs/CV6P0625.pdf Article link]
==See also==
*[[Darzens-Nenitzescu synthesis of ketones]]
*[[Nencki reaction]]
[[Category:Substitution reactions]]
[[Category:Carbon-carbon bond forming reactions]]
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