Friedel-Crafts reaction

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The Friedel-Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877.[1] There are two main types of Friedel-Crafts reactions: alkylation reactions and acylation reactions. This reaction type is part of electrophilic aromatic substitution.

The Friedel-Crafts alkylation of benzene with methyl chloride

Several reviews have been written.[2][3][4][5]

Contents

[edit] Friedel-Crafts alkylation

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.

Mechanism for the Friedel Crafts alkylation

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 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.

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:[6]

Friedel-Crafts alkylation by an alkene

In this reaction samarium(III) triflate is believed to activate the NBS halogen donor in halonium ion formation.

[edit] 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 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.[7] 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 equilibration. The ultimate reaction product is thus the result of a series of alkylations and dealkylations.

synthesis of 2,4,6-triethylbenzene

[edit] 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 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.

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 Synthesis, accomplished by reacting benzene with carbon monoxide and hydrogen chloride under high pressure, catalyzed by a mixture of aluminium chloride and cuprous chloride.

[edit] Reaction mechanism

In a simple mechanistic view, the first step consists of dissociation of a chlorine atom to form an acyl cation:

FC acylation step 1

This is followed by nucleophilic attack of the arene toward the acyl group:

FC acylation step II

Finally, a chlorine atom reacts to form HCl, and the AlCl3 catalyst is regenerated:

FC acylation step III

[edit] Friedel-Crafts hydroxyalkylation

Arenes react with certain aldehydes and ketones to the hydroxyalkylated product for example in the reaction of the mesityl derivative of glyoxal with benzene[8] to form a benzoin with an alcohol rather than a carbonyl group:

Friedel-Crafts hydroxyalkylaiton

[edit] Scope & variations

This reaction is related to several classic named reactions:


[edit] Dyes

Friedel-Crafts reactions have been used in the synthesis of several triarylmethane and xanthene dyes [13]. Examples are the synthesis of thymolphthalein (a pH indicator) from two equivalents of thymol and phthalic anhydride:

Thymolphthalein Synthesis

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:

Rhodamine B synthesis

[edit] References

  1. ^ Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392 & 1450.
  2. ^ Price, C. C. Org. React. 1946, 3, 1. (Review)
  3. ^ Groves, J. K. Chem. Soc. Rev. 1972, 1, 73. (Review)
  4. ^ Eyley, S. C. Comp. Org. Syn. 1991, 2, 707-731. (Review)
  5. ^ Heaney, H. Comp. Org. Syn. 1991, 2, 733-752. (Review)
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ This reaction with phosphorus pentoxide: J. v. d. Kamp and E. Mosettig (1936). "TRANS- AND CIS-AS-OCTAHYDROPHENANTHRENE". J. Am. Chem. Soc. 58 (6): 1062-1063. doi:10.1021/ja01297a514. 
  10. ^ Darzens-Nenitzescu Synthesis of Ketones
  11. ^ Nenitzescu Reductive Acylation
  12. ^ Sereda, Grigoriy A.; Rajpara, Vikul B. (2007). "A Green Alternative to Aluminum Chloride Alkylation of Xylene". J. Chem. Educ. 2007 (84): 692. 
  13. ^ Synthesis of Triarylmethane and Xanthene Dyes Using Electrophilic Aromatic Substitution Reactions James V. McCullagh and Kelly A. Daggett J. Chem. Educ. 2007, 84, 1799. Abstract


[edit] FC reactions in Org. Synth.

Friedel-Crafts reactions appear in Organic Syntheses:

[edit] See also

  • Darzens-Nenitzescu synthesis of ketones
  • Nencki reaction