Electrophilic acylations Friedel-Crafts reactions

In Friedel-Crafts acylations, an acyl halide, almost always the chloride, in the presence of a Lewis acid is employed to acylate an aromatic ring. The process is initiated by polarization of the carbon-chlorine bond of the acyl chloride, resulting in formation of a resonance-stabilized acylium ion. 

The acylium ion is now our electrophile, and aromatic substitution proceeds in the predicted manner. 

The intermediate cation is subsequently deproto-nated to yield the acylated product. However, this acyl derivative is actually a ketone, which can also complex with the Lewis acid. Accordingly, the final 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

A useful extension of Friedel-Crafts acylation is an intramolecular reaction leading to cyclic products. Thus, five- and six-membered rings are readily and efficiently created by use of an appropriate aryl acyl chloride, as shown below. 

---

Know the meaning of electrophilic aromatic substitution, halogenation, nitration, sulfonation, alkylation, acylation, Friedel-Crafts reaction. 

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... 

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). 

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... 

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

By this strategy, reactive carbon electrophiles can be generated for successful reaction with a variety of weak carbon nucleophiles. More important examples include the Friedel-Crafts reaction in which aromatic compounds (nucleophiles) react with alkyl and acyl halides (electrophiles in the presence of Lewis acids). 

Related classes of gitonic superelectrophiles are the previously mentioned protoacetyl dications and activated acyl cationic electrophiles. The acyl cations themselves have been extensively studied by theoretical and experimental methods,22 as they are intermediates in many Friedel-Crafts reactions. Several types of acyl cations have been directly observed by spectroscopic methods and even were characterized by X-ray crystal structure analysis. Acyl cations are relative weak electrophiles as they are effectively stabilized by resonance. They are capable of reacting with aromatics such as benzene and activated arenes, but do not generally react with weaker nucleophiles such as deactivated arenes or saturated alkanes. 

Aromatic compounds react mainly by electrophilic aromatic substitution, in which one or more ring hydrogens are replaced by various electrophiles. Typical reactions are chlorination, bromination, nitration, sulfonation, alkylation, and acylation (the last two are Friedel-Crafts reactions). The mechanism involves two steps addition of the electrophile to a ring carbon, to produce an intermediate benzenonium ion, followed by proton loss to again achieve the (now substituted) aromatic system. 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201. 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friedel-Crafts reactions (201, 236. 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

Treatment of saturated azlactones with aromatic compounds under Friedel-Crafts conditions gives acylamino ketones in high yield (equation 46). 4-Benzyl-2-methyl-5(4H)-oxazolone undergoes an intramolecular reaction to yield an acetamidoindanone (equation 47). Friedel-Crafts reactions of 4-(arylmethylene)-5(4H)-oxazolones are complicated by the presence of an additional electrophilic centre (cf. 201) and may follow three courses. The unsaturated azlactone (189) adds benzene under the influence of aluminum chloride to form the saturated azlactone (207) in inert solvents (189) undergoes an intramolecular acylation to yield a mixture of the indenone (208) and the isoquinoline (209 Scheme 20). 

In retrospect, it is ironic to it that when I met Ernst Schumacher in 1969 (he was then Professor at the University of Bern in Switzerland) we did not talk about the experiments he did at Zurich in the same building where I was at that time. Instead, his interest focussed on our work on borazine transition metal compounds and we discussed in some detail whether it would be possible to incorporate metal atoms like chromium or molybdenum between the layers of hexagonal boron nitride (BN) in a similar way as it can be done with graphite. In the course of these discussions I did not mention that, after I had moved to Zurich, we had begun to investigate the reactivity of nickelocene towards both nucleophilic and electrophilic substrates. The reason was that we were still at the beginning, and while we had been able to prepare a series of monocyclopentadienyl nickel complexes from Ni(C5H5)2 and Lewis bases, our attempts to obtain alkyl- or acyl-substituted nickelocenes by the Friedel-Crafts reaction failed. 

Attempts to prepare a monoketone also failed with 10-ethyl- and 10-phenylphenothiazine. There is evidence, derived primarily from UV spectra, that 2,7-diketones are the products when 3,10-dialkyl-phenothiazines undergo Friedel-Crafts acylation. The best yields of diketones are obtained, as expected, when a 1 2 molar ratio of AICI3 and acetic anhydride is used, because the catalyst is involved here only in the generation of the electrophilic agent of the Friedel-Crafts reaction, unlike with the 10-acyl derivatives where it also forms a complex lO-acylphenothiazine-AlCls. ... 

In a similar manner, acyl carbocations formed from acyl halides act as an electrophile in Friedel-Crafts acylation reactions (Scheme 2.3). 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

Electrophiles for aromatic substitution include the halonium ion, the nitronium ion and the carbonium ion. The latter may be generated from alkyl and acyl halides using Lewis acid catalysis in the Friedel-Crafts reactions. 

Direct Reactions with Electrophiles at C-5. Vilsmeier and Friedel-Crafts reactions lead to 5-acyl derivatives (eq 3), which can be further elaborated as indicated in eq 4 a single enantiopure diastereoisomer of the anhydride (4) is formed. Seebach and co-workers erroneously assigned (4) as arising from an exo rather than the endo addition. 

There are no reported alternatives to the current procedure for the acylation of a phenanthrene using the Friedel-Crafts reaction. Indeed, alternative methods to cleanly prepare 3,6-disubstituted derivatives of phenanthrene by means of electrophilic substitution are not known,5> >" nor is there a... 

All of the Friedel-Crafts reactions discussed thus far have resulted from intermolecular reaction of a benzene ring with an electrophile. Starting materials that contain both units are capable of intramolecular reaction, and this forms a new ring. For example, treatment of compound A, which contains both a benzene ring and an acid chloride, with AICI3, forms a-tetralone by an intramolecular Friedel-Crafts acylation reaction. 

New C—C bonds to arenes can be made by Friedel-Crafts reactions. Friedel-Crafts alkylations are traditionally executed with an alkyl chloride and catalytic AICI3 or an alkene and a strong Brpnsted or Lewis acid the key electrophilic species is a carbocation. Friedel-Crafts acylations are usually executed with an acyl chloride and an excess of AICI3 the key electrophilic species is an acylium ion (RC=0+). In the Bischler-Napieralski reaction, intramolecular attack on a nitrilium ion (RC=NR) occurs. 

The Friedel-Crafts reaction includes both alkylation and acylation although here only acylation is exemplified. For the Friedel-Crafts acylation, the electrophile could be either an acid chloride or an anhydride. The catalyst could be either a Lewis or protic acid. 

The Heck reaction makes a C-C bond and adds a highly functionalised fragment that can be elaborated into many other functional groups. The same is true of the Friedel-Crafts reaction that generally works well with azoles or other heterocycles able to do electrophilic substitution. As usual, it is best to have only one free position so that no regioselectivity problems arise. In the Heck reaction, the site of attack is marked by the iodine atom, but the Friedel-Crafts can occur at any free position. Our example is a pyrazole that acylates cleanly with Lewis acid catalysts to give eventually the herbicide pyrazolate 196. 

The well-established stabilization of a positive charge on carbon p to silicon has been utilized in very versatile methods for the control of aliphatic Friedel-Crafts reactions. The specificity of this stabilization lies behind the utility of both alkenyl- and allyl-silanes as substrates for electrophilic substitutions, and acylations in particular. These classes offer complementary regiospecificities in controlling both the site of acylation and the location of the double bond. This promotion of simple substitution is one of the most significant advances in aliphatic Friedel-Crafts acylations of recent times, and has recently been the subject of an exhaustive review. ... 

---