| Friedel-Crafts reaction | |||||||||
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| Named after | Charles Friedel James Crafts | ||||||||
| Reaction type | Coupling reaction | ||||||||
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| RSC ontology ID | RXNO:0000369 | ||||||||
TheFriedel–Crafts reactions are a set ofreactions developed byCharles Friedel andJames Crafts in 1877 to attach substituents to anaromatic ring.[1] Friedel–Crafts reactions are of two main types:alkylation reactions andacylation reactions. Both proceed byelectrophilic aromatic substitution.[2][3][4][5]
| Friedel-Crafts alkylation | |||||||||||
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| Named after | Charles Friedel James Crafts | ||||||||||
| Reaction type | Coupling reaction | ||||||||||
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| Organic Chemistry Portal | friedel-crafts-alkylation | ||||||||||
| RSC ontology ID | RXNO:0000046 | ||||||||||
In commercial applications, the alkylating agents are generallyalkenes, some of the largest scale reactions practiced in industry. Such alkylations are of major industrial importance, e.g. for the production ofethylbenzene, the precursor to polystyrene, from benzene and ethylene and for the production of cumene from benzene and propene incumene process:
Industrial production typically usessolid acids derived from azeolite as the catalyst.
Friedel–Crafts alkylation involves thealkylation of anaromatic ring. Traditionally, the alkylating agents arealkyl halides. Many alkylating agents can be used instead of alkyl halides. For example,enones andepoxides can be used in presence of protons. The reaction typically employs a strongLewis acid, such asaluminium chloride as catalyst, to increase the electrophilicity of the alkylating agent.[6]
This reaction suffers from the disadvantage that the product is morenucleophilic than the reactant because alkyl groups areactivators for the Friedel–Crafts reaction. Consequently, overalkylation can occur. However,steric hindrance can be exploited to limit the number of successive alkylation cycles that occur, as in thet-butylation of 1,4-dimethoxybenzene that gives only the product of two alkylation cycles and with only one of three possible isomers of it:[7]
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 totertiary 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 acarbocationrearrangement reaction to give almost exclusively the rearranged product derived from a secondary or tertiary carbocation.[8]
Protonation of alkenes generatescarbocations, the electrophiles. A laboratory-scale example by the synthesis ofneophyl chloride from benzene andmethallyl chloride usingsulfuric acid catalyst.[9]
The general mechanism for primary alkyl halides is shown in the figure below.[8]
Friedel–Crafts alkylations can bereversible. Although this is usually undesirable it can be exploited; for instance by facilitatingtransalkylation reactions.[10]
It also allows alkyl chains to be added reversibly asprotecting groups. This approach is used industrially in the synthesis of4,4'-biphenol via the oxidative coupling and subsequent dealkylation of2,6-di-tert-butylphenol.[11][12]
| Friedel-Crafts acylation | |||||||||||
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| Reaction type | Coupling reaction | ||||||||||
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| Organic Chemistry Portal | friedel-crafts-acylation | ||||||||||
| RSC ontology ID | RXNO:0000045 | ||||||||||
Friedel–Crafts acylation involves theacylation of aromatic rings. Typical acylating agents areacyl chlorides.Acid anhydrides as well as carboxylic acids are also viable. A typicalLewis acid catalyst isaluminium trichloride. Because, however, the product ketone forms a rather stable complex with Lewis acids such as AlCl3, a stoichiometric amount or more of the "catalyst" must generally be employed, unlike the case of the Friedel–Crafts alkylation, in which the catalyst is constantly regenerated.[13] Reaction conditions are similar to the Friedel–Crafts alkylation. This reaction has several advantages over the alkylation reaction. Due to the electron-withdrawing effect of thecarbonyl group, theketone product is always less reactive than the original molecule, so multiple acylations do not occur. Also, there are nocarbocation rearrangements, as theacylium 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 ofbenzaldehyde through the Friedel–Crafts pathway requires that formyl chloride be synthesizedin situ. This is accomplished by theGattermann-Koch reaction, accomplished by treating benzene withcarbon monoxide andhydrogen chloride under high pressure, catalyzed by a mixture ofaluminium chloride andcuprous chloride. Simple ketones that could be obtained by Friedel–Crafts acylation are produced by alternative methods, e.g., oxidation, in industry.
The reaction proceeds through generation of an acylium center. The reaction is completed by deprotonation of thearenium 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.[14] In certain cases, generally when the benzene ring is activated, Friedel–Crafts acylation can also be carried out withcatalytic 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 eitherWolff–Kishner reduction orClemmensen reduction. The net result is the same as the Friedel–Crafts alkylation except that rearrangement is not possible.[15]
Arenes react with certainaldehydes and ketones to form the hydroxyalkylated products, for example in the reaction of themesityl derivative ofglyoxal with benzene:[16]
As usual, the aldehyde group is more reactive electrophile than thephenone.
This reaction is related to several classic named reactions:
Friedel–Crafts reactions have been used in the synthesis of severaltriarylmethane andxanthenedyes.[26] Examples are the synthesis ofthymolphthalein (a pH indicator) from two equivalents ofthymol andphthalic anhydride:
A reaction of phthalic anhydride withresorcinol in the presence ofzinc chloride gives the fluorophorefluorescein. Replacing resorcinol by N,N-diethylaminophenol in this reaction givesrhodamine B:
TheHaworth synthesis is a classic method for the synthesis of polycyclic aromatic hydrocarbons. In this reaction, anarene is reacted withsuccinic anhydride, the subsequent product is then reduced in either aClemmensen reduction or aWolff-Kishner reduction. Lastly, a second Friedel-Crafts acylation takes place with addition of acid.[27]
The product formed in this reaction is then analogously reduced, followed by a dehydrogenation reaction (with the reagentSeO2 for example) to extend the aromatic ring system.[28]
Reaction ofchloroform with aromatic compounds using analuminium chloride catalyst gives triarylmethanes, which are often brightly colored, as is the case in triarylmethane dyes. This is a bench test for aromatic compounds.[29]
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