- Friedel-Crafts reaction
The Friedel-Crafts reactions are a set of reactions developed by
Charles Friedeland James Craftsin 1877. [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] .] There are two main types of Friedel-Crafts reactions: alkylationreactions and acylationreactions. This reaction type is part of electrophilic aromatic substitution.
Several reviews have been written. [Price, C. C. "Org. React." 1946, "3", 1. (Review)] [Groves, J. K. "
Chem. Soc. Rev." 1972, "1", 73. (Review)] [Eyley, S. C. "Comp. Org. Syn." 1991, "2", 707-731. (Review)] [Heaney, H. "Comp. Org. Syn." 1991, "2", 733-752. (Review)]
Friedel-Crafts alkylation involves the alkylation of an
aromatic ringand an alkyl halideusing a strong Lewis acidcatalyst. With anhydrous ferric chlorideas a catalyst, the alkyl group attaches at the former site of the chloride ion.
This reaction has one big disadvantage, namely that the product is more 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 reactionwill occur. This is due to the relative stability of the tertiary carbocationover the secondary and primary carbocations. Steric hindrancecan be exploited to limit the number of alkylations, as in the t-butylation of 1,4-dimethoxybenzene.
Alkylations are not limited to alkyl halides: Friedel-Crafts reactions are possible with any
carbocationic intermediate such as those derived from alkenes and a protic acidor lewis acid, enones and epoxides. In one study the electrophile is a bromonium ionderived from an alkene and NBS: [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]
In this reaction
samarium(III) triflateis believed to activate the NBS halogen donor in halonium ion formation.
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 ethyl bromide to
benzene, "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 meta substituent. [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 | volume = 2005| issue = 12 | pages = 2080–2083 | doi = 10.1055/s-2005-869963] Thermodynamic reaction controlmakes sure that thermodynamically favored "meta" substitution with steric hindranceminimized takes prevalence over less favorable "ortho" and "para" substitution by chemical equilibration. The ultimate reaction product is thus the result of a series of alkylations and dealkylations.
Friedel-Crafts acylation is the
acylationof aromatic rings with an acyl chlorideusing a strong Lewis acidcatalyst. Friedel-Crafts acylation is also possible with acid anhydrides. 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 carbonylgroup, the ketoneproduct is always less reactive than the original molecule, so multiple acylations do not occur. Also, there are no carbocationrearrangements, as the carbonium 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
benzaldehydevia the Friedel-Crafts pathway requires that formyl chloride be synthesized "in situ". This is accomplished via the Gattermann-Koch reaction, accomplished by reacting benzenewith carbon monoxideand hydrogen chlorideunder high pressure, catalyzed by a mixture of aluminium chlorideand cuprous chloride.
In a simple mechanistic view, the first step consists of dissociation of a chlorine atom to form an
This is followed by nucleophilic attack of the arene toward the acyl group:
Finally, a chlorine atom reacts to form HCl, and the AlCl3 catalyst is regenerated:
Arenes react with certain
aldehydes and ketones to the hydroxyalkylated product for example in the reaction of the mesitylderivative of glyoxalwith benzene [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] to form a benzoinwith an alcoholrather than a carbonylgroup:
cope & variations
This reaction is related to several classic named reactions:
* The acylated reaction product can be converted into the alkylated product via a
Gattermann-Koch reactioncan be used to synthesize benzaldehyde from benzene.
Gatterman reactiondescribes arene reactions with hydrocyanic acid
Houben-Hoesch reactiondescribes arene reactions with nitriles
* A reaction modification with an aromatic phenyl ester as a reactant is called the
* In the
Scholl reactiontwo arenes couple directly (sometimes called Friedel-Crafts arylation).
* In the
Zincke-Suhl reactionp-cresol is alkylated to a cyclohexadienone with tetrachloromethane
* In the
Blanc chloromethylationa chloromethyl group is added to an arene with formaldehyde, hydrochloric acid and zinc chloride.
* The Bogert-Cook Synthesis (1933) involves the
dehydrationand isomerizationof "1-β-phenylethylcyclohexanol" to the octahydro derivative of phenanthrene[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 ]
* The Darzens-Nenitzescu Synthesis of Ketones (1910, 1936) [ [http://www.drugfuture.com/OrganicNameReactions/onr94.htm Darzens-Nenitzescu Synthesis of Ketones ] ] involves the acylation of
cyclohexenewith acetyl chlorideto methylcyclohexenylketone.
* In the related Nenitzescu reductive acylation (1936) [ [http://www.drugfuture.com/OrganicNameReactions/onr277.htm Nenitzescu Reductive Acylation ] ] a
saturated hydrocarbonis added making it a reductive acylation to methylcyclohexylketone
* In a
green chemistryvariation aluminium chlorideis replaced by graphitein an alkylation of "p"-xylene with 2-bromobutane. This variation will not work with primary halides from which less carbocation involvement is inferred. [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]
Friedel-Crafts reactions have been used in the synthesis of several triarylmethane and
xanthene dyes ["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] ] . Examples are the synthesis of thymolphthalein(a pH indicator) from two equivalents of thymoland phthalic anhydride:
A reaction of phthalic anhydride with
resorcinolin the presence of zinc chloridegives the fluorophore Fluorescein. Replacing resorcinol by N,N-diethylaminophenol in this reaction gives rhodamine B:
The Haworth reaction is a classic method for the synthesis of
tetralone["Syntheses of alkylphenanthrenes. Part I. 1-, 2-, 3-, and 4-Methylphenanthrenes"Robert Downs Haworth, J. Chem. Soc.1932, 1125 DOI|10.1039/JR9320001125] ["Name Reactions: A Collection of Detailed Reaction Mechanisms" By Jie Jack Li Published 2003 Springer ISBN 3540402039] . In it benzeneis reacted with succinic anhydride, the intermediate product is reduced and a second FC acylation takes place with addition of acid.
In a related reaction,
phenanthreneis synthesized from naphthaleneand succinic anhydridein a series of steps.
FC reactions in Org. Synth.
Friedel-Crafts reactions appear in
** 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
chloromethaneto dureneOrganic Syntheses, Coll. Vol. 2, p.248 (1943); Vol. 10, p.32 (1930). [http://orgsynth.org/orgsyn/pdfs/CV2P0248.pdf Article link]
** Synthesis of
benzophenonefrom benzeneand tetrachloromethaneOrganic Syntheses, Coll. Vol. 1, p.95 (1941); Vol. 8, p.26 (1928). [http://orgsynth.org/orgsyn/pdfs/CV1P0095.pdf Article link]
** 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
acenaphtheneplus succinic acidOrganic 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
phenanthrenecompound Organic Syntheses, Vol. 80, p.227 [http://orgsynth.org/orgsyn/pdfs/v80p0227.pdf Link]
** Reaction of
bromobenzenewith acetic anhydrideOrganic 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
ferroceneOrganic Syntheses, Coll. Vol. 6, p.625 (1988); Vol. 56, p.28 (1977). [http://orgsynth.org/orgsyn/pdfs/CV6P0625.pdf Article link]
Darzens-Nenitzescu synthesis of ketones
Wikimedia Foundation. 2010.