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.
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 overalkyation of the molecule. Also, if the chlorine is not on a tertiary carbon, carbocationrearrangement 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.
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 acid or lewis acid, enones and epoxides. In one study the electrophile is a bromonium ion derived from an alkene and NBS:
In this reaction samarium(III) triflate is 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.
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 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 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.
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 Synthesis, accomplished by reacting benzene with carbon monoxide and hydrogen chloride under high pressure, catalyzed by a mixture of aluminium chloride and cuprous chloride.
In a simple mechanistic view, the first step consists of dissociation of a chlorine atom to form an acyl cation:
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 mesityl derivative of glyoxal with benzene to form a benzoin with an alcohol rather than a carbonyl group:
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.
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.
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^ Heaney, H. Comp. Org. Syn.1991, 2, 733-752. (Review)
^ S. Hajra, B. Maji and S. Bar (2007). "Samarium Triflate-Catalyzed Halogen-Promoted Friedel-Crafts Alkylation with Alkenes". Org. Lett.9 (15): 2783-2786. doi:10.1021/ol070813t.
^ K. Wallace, R. Hanes, E. Anslyn, J. Morey, K. Kilway and J. Siegel (2005). "Preparation of 1,3,5-Tris(aminomethyl)-2,4,6-triethylbenzene from Two Versatile 1,3,5-Tri(halosubstituted) 2,4,6-Triethylbenzene Derivatives". Synthesis (12): 2080-2083. doi:10.1055/s-2005-869963.
^ R. C. Fuson, H. H. Weinstock and G. E. Ullyot (1935). "A New Synthesis of Benzoins. 2′,4′,6′-Trimethylbenzoin". J. Am. Chem. Soc.57 (10): 1803-1804. doi:10.1021/ja01313a015.