Friedel-Crafts reaction electrophiles

CI2, FeClj, FeBr3(anhydrous) Friedel-Crafts reaction/ electrophilic substitution in an arene CsHs CgHsCI... 

The most widely used reactions are those of electrophilic substitution, and under controlled conditions a maximum of three substituting groups, e.g. -NO2 (in the 1,3,5 positions) can be introduced by a nitric acid/sul-phuric acid mixture. Hot cone, sulphuric acid gives sulphonalion whilst halogens and a Lewis acid catalyst allow, e.g., chlorination or brom-ination. Other methods are required for introducing fluorine and iodine atoms. Benzene undergoes the Friedel-Crafts reaction. ... 

Laurino examined a similar method in which methanesulfonanilides were alkylated with bromoacetaldehyde diethyl acetal and then cyclized with TiCU[4J. 1 hese methods presumably involve generation of an electrophilic intermediate from the acetal functionality, followed by an intramolecular Friedel-Crafts reaction. As a consequence, the cyclization is favoured by ER substituents and retarded by EW groups on the benzene ring. 

Electrophilic aromatic substitution (Sec tion 22 14) Arylamines are very reac tive toward electrophilic aromatic sub stitution It IS customary to protect arylamines as their N acyl derivatives before carrying out ring nitration chio rination bromination sulfonation or Friedel-Crafts reactions... 

Whereas the above reactions are appHcable to activated aromatics, deactivated aromatics can be formylated by reaction with hexamethylenetetramine in strong acids such as 75% polyphosphoric acid, methanesulfonic acid, or trifluoroacetic acid to give saUcylaldehyde derivatives (117). Formyl fluoride (HCOF) has also been used as formyl a ting agent in the Friedel-Crafts reaction of aromatics (118). Formyl fluoride [1493-02-3] in the presence of BF was found to be an efficient electrophilic formyl a ting agent, giving 53% para-, 43% ortho- and 3.5% meta-tolualdehydes upon formylation of toluene (110). 

Friedel-Crafts acylation using nittiles (other than HCN) and HCI is an extension of the Gattermann reaction, and is called the Houben-Hoesch reaction (120—122). These reactions give ketones and are usually appHcable to only activated aromatics, such as phenols and phenoHc ethers. The protonated nittile, ie, the nitrilium ion, acts as the electrophilic species in these reactions. Nonactivated ben2ene can also be acylated with the nittiles under superacidic conditions 95% trifluoromethanesulfonic acid containing 5% SbF (Hg > —18) (119). A dicationic diprotonated nittile intermediate was suggested for these reactions, based on the fact that the reactions do not proceed under less acidic conditions. The significance of dicationic superelectrophiles in Friedel-Crafts reactions has been discussed (123,124). 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

Beyer synthesis, 2, 474 electrolytic oxidation, 2, 325 7r-electron density calculations, 2, 316 1-electron reduction, 2, 282, 283 electrophilic halogenation, 2, 49 electrophilic substitution, 2, 49 Emmert reaction, 2, 276 food preservative, 1,411 free radical acylation, 2, 298 free radical alkylation, 2, 45, 295 free radical amidation, 2, 299 free radical arylation, 2, 295 Friedel-Crafts reactions, 2, 208 Friedlander synthesis, 2, 70, 443 fluorination, 2, 199 halogenation, 2, 40 hydrogenation, 2, 45, 284-285, 327 hydrogen-deuterium exchange, 2, 196, 286 hydroxylation, 2, 325 iodination, 2, 202, 320 ionization constants, 2, 172 IR spectra, 2, 18 lithiation, 2, 267... 

The Friedel-Crafts reaction is a very important method for introducing alkyl substituents on an aromatic ring. It involves generation of a carbocation or related electrophilic species. The most common method of generating these electrophiles involves reaction between an alkyl halide and a Lewis acid. The usual Friedel-Crafts catalyst for preparative work is AICI3, but other Lewis acids such as SbFj, TiC, SnCl4, and BF3 can also promote reaction. Alternative routes to alkylating ecies include protonation of alcohols and alkenes. 

Absolute rate data for Friedel-Crafts reactions are difficult to obtain. The reaction is complicated by sensitivity to moisture and heterogeneity. For this reason, most of the structure-reactivity trends have been developed using competitive methods, rather than by direct measurements. Relative rates are established by allowing the electrophile to compete for an excess of the two reagents. The product ratio establishes the relative reactivity. These studies reveal low substrate and position selectivity. 

A good deal of experimental care is often required to ensure that the product mixture at the end of a Friedel-Crafts reaction is determined by kinetic control. The strong Lewis acid catalysts can catalyze the isomerization of alkylbenzenes, and if isomerization takes place, the product composition is not informative about the position selectivity of electrophilic attack. Isomerization increases the amount of the meta isomer in the case of dialkylbenzenes, because this isomer is thermodynamically the most stable. ... 

Alcohols and alkenes can also serve as sources of electrophiles in Friedel-Crafts reactions in the presence of strong acids ... 

Isoxazoles are known at present to undergo the following electrophilic substitution reactions nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, and mercuration. Repeated attempts to effect the Friedel-Crafts reaction in the isoxazole series in the authors laboratory failed. The isoxazole nucleus seems not active enough to react with weak electrophilic reagents. 

The rate-determining step is the electrophilic aromatic substitution as in the closely related Friedel-Crafts reaction. Both reactions have in common that a Lewis acid catalyst is used. For the Blanc reaction zinc chloride is generally employed, and the formation of the electrophilic species can be formulated as follows ... 

Among the most useful electrophilic aromatic substitution reactions In the laboratory is alkylation—the introduction of an alkyl group onto the benzene ring. Called the Friedel-Crafts reaction after its discoverers, the reaction is carried out... 

Yet a final limitation to the Friedel-Crafts reaction is that a skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs during reaction, particularly when a primary alkyl halide is used. Treatment of benzene with 1-chlorobutane at 0 °C, for instance, gives an approximately 2 1 ratio of rearranged (sec-butyl) to unrearranged (butyl) products. 

Figure 16.10 Biosynthesis of phylloquinone (vitamin K-j) from 1,4-dihydroxynaphthoic acid. The key step that joins the 20-carbon phytyl side chain to the aromatic ring is a Friedel-Crafts-like electrophilic substitution reaction.

The carbocation electrophile in a Friedel-Crafts reaction can be generated in ways other than by reaction of an alkyl chloride with AICI3. For example, reaction of benzene with 2-methylpropene in the presence of H3PO4 yields tert-butylbenzene. Propose a mechanism for this reaction. 

Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel-Crafts reactions are not successful (Section 16.3). The amino group forms an acid-base complex with the AICI3 catalyst, which prevents further reaction from occurring. Both drawbacks can be overcome, however, b3 carrying out electrophilic aromatic substitution reactions on the corresponding amide rather than on the free amine. 

Unlike benzene, pyridine undergoes electrophilic aromatic substitution reactions with great difficulty. Halogenation can be carried out under drastic conditions, but nitration occurs in very low yield, and Friedel-Crafts reactions are not successful. Reactions usually give the 3-substituted product. 

Friedel-Crafts reaction (Section 16.3) An electrophilic aromatic substitution reaction to alkylate or acylate an aromatic ring. 

In principle, sulfonyl compounds bearing highly-electron-accepting substituents are able to transfer the sulfonyl group as an electrophile. Thus, the exchange of aryl substituents in methyl aryl sulfones under catalysis of trifluoromethanesulfonic acid takes place258 (equation 46). This reaction represents a further example for the reversibility of Friedel-Crafts reactions. 

As described above, propargylic alcohols can serve as electrophilic aUcyl equivalents in intermolecular Friedel-Crafts reactions. However, the related intramolecular... 

There are a number of variations of the Friedel-Crafts reactions that are useful in synthesis. The introduction of chloromethyl substituents is brought about by reaction with formaldehyde in concentrated hydrochloric acid and halide salts, especially zinc chloride.62 The reaction proceeds with benzene and activated derivatives. The reactive electrophile is probably the chloromethylium ion. 

There are certain formal analogies here to m- attack on nitrobenzene (cf. p. 152), but pyridine is very much more difficult to substitute than the former. Thus nitration, chlorination, bromination and Friedel-Crafts reactions cannot really be made to take place usefully, and sulphonation only occurs on heating with oleum for 24 hours at 230°, with an Hg2 catalyst. This difficulty of attack is due partly to the fact that pyridine has an available electron pair on nitrogen, and can thus protonate (66), or interact with an electrophile (67) ... 

Its aromaticity cannot, of course, be tested by attempted electrophilic substitution, for attack by X would merely lead to direct combination with the anion. True aromatic character (e.g. a Friedel-Crafts reaction) is, however, demonstrable in the remarkable series of extremely stable, neutral compounds obtainable from (15), and called metallocenes, e.g. ferrocene (16), in which the metal is held by n bonds in a kind of molecular sandwich between the two cyclopentadienyl structures ... 

Aromaticity of 2,4,6-tri-fert-butylphenylphosphole (17d) was also revealed in chemical reactions phosphole 17d could undergo aromatic electrophilic substitution. In reaction with acetyl chloride, a mixture of 2-, 4-, and 5-acetyl phospholes (23a, 24a, and 25a, respectively), as well as a diacetyl derivative (26a) were formed (Scheme 6) [39], Interestingly, the most crowded 2-acetyl derivative (23a) was the main product of the Friedel-Crafts reaction. A similar situation was observed for 3-methylpyrrol [46],... 

Mesoxalates are highly reactive substrates because of their strongly polarized carbon-oxygen bond. They have been used in pericyclic processes (e.g. Diels-Alder reactions,8 ene reactions,9 [3+2]10 and [2+2]11 cycloadditions), in aldol12 and Wittig as well as Friedel-Crafts reactions.13 Further applications arise from the use of the corresponding imines in hetero Diels-Alder reactions14 and electrophilic cyclizations.15... 

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