Friedel–Crafts reaction: Difference between revisions

The Friedel–Crafts reactions are a set of

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]

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.

With Alkenes

In commercial applications, the alkylating agents are generally alkenes. 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]

Such alkylations are of major industrial importance, e.g. for the production of ethylbenzene, the precursor to polystyrene, from benzene and ethylene:

Industrial production typically uses solid acids derived from a zeolite as the catalyst.

Friedel–Crafts dealkylation

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

Acylation

Friedel–Crafts acylation involves the

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

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

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

Scope and variations

This reaction is related to several classic named reactions:

• The acylated reaction product can be converted into the alkylated product via a
  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
  2-bromobutane. This variation will not work with primary halides from which less carbocation involvement is inferred.^[23]

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

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]

See also

• Ethylene oxide
• Friedel family, a rich lineage of French scientists
• Hydrodealkylation
• Transalkylation

References