Friedel-Crafts Acylation and Related Reactions

Friedel-Crafts acylation usually involves the reaction of an acyl halide a Lewis acid catalyst, and the aromatic substrate. Two possible electrophiles can be envisaged. A discrete positively charged acylium ion can be formed and act as the electrophile, or the active electrophile could be a complex formed between the acyl halide and the Lewis acid catalyst. 

The formation of acyl halide-Lewis acid complexes can be demonstrated readily. Acetyl chloride, for example, forms both 1 1 and 1 2 complexes with AICI3 which can be observed by NMR. The existence of acylium ions has been demonstrated by X-ray diffraction studies on crystalline salts. For example, crystal structure determinations have been reported for p-methylphenylacylium and methyl-acylium (acetylium) ions as SbF salts. There is also a good deal of evidence from NMR measurements which demonstrates that acylium ions can exist in non-nucleophilic solvents. The positive charge on acylium ions is delocalized onto the oxygen atom. This delocalization is demonstrated in particular by the short O—C bond lengths in acylium ions, which imply a major contribution from the structure having a triple bond  

As is the case with Friedel-Crafts alkylations, direct kinetic measurements are difficult, and not many data are available. Rate equations of the form 

One other feature of the data in Table 10.10 is worthy of further comment. Notice that alkyl (acetyl, propionyl) substituted acylium ions exhibit a smaller o p ratio than the various aroyl systems. If steric factors were dominating the position selectivity, one would expect the opposite result. A possible explanation for this feature of the data could be that the aryl compounds are reacting via free acylium ions, whereas the alkyl systems may involve more bulky acid chloride-catalyst complexes. Steric factors clearly enter into determining the o p ratio. The hindered 2,4,6-trimethylbenzoyl group is introduced with a 50 1 preference for the para position. Similarly, in the benzoylation of alkylbenzenes by benzoyl chloride-aluminum chloride, the amount of ortho product decreases (10.3%, 6.0%, 3.1%, 0.6%, respectively) as the branching of the alkyl group is increased along the series methyl, ethyl, 2-propyl, t-butyl.  

Friedel-Crafts acylation sometimes shows a modest kinetic isotope effect. This observation suggests that the proton removal is not much faster than the formation of the a complex and that the formation of the a complex may be reversible under some conditions. 

Aryl acyhum ions have substantial charge delocalization into the aromatic ring. 

This provides unequivocal evidence that the acylium ion can act as the active electrophile. 

Steric factors clearly enter into determining the ortho para ratio. The hindered 2,4,6-trimethylbenzoyl group is introduced with a 50 1 preference for the para position. Similarly, in the benzoylation of alkylbenzenes by benzoyl chloride-aluminum chloride, the amount of ortho product decreases (10.3%, 6.0%, 3.1%, 0.6%, respectively) as the branching of the alkyl group is increased along the series methyl, ethyl, i-propyl, t-butyl.  

One other feature of the data in Table 10.10 is worthy of further comment. Notice that alkyl substituted acyhum ions exhibit a smaller ortho para ratio than the various aroyl systems. If steric factors were dominating the position selectivity, one would expect the opposite result. A possible explanation for this feature of the data could be that the aryl compoimds are reacting via free acyhum ions, whereas the alkyl systems may involve more bulky acyl chloride-catalyst complexes. 

Rate = A i[RCOCl-AlCl3][ArH] + fezERCOCl-AlCljl CArH] 

The existence of acylium salts has been demonstrated by X-ray diffraction studies on crystalline salts. For example, crystal structure determinations have been 

Acetyl chloride-AlCl3 Propionyl chloride-AlCls CHsteO SbFe  

The existence of acylium ions has been demonstrated by X-ray diffraction studies on crystalline salts. For example, crystal structure determinations have been reported for p-methylphenyloxocarbonium (SbCL salt) and acetylium (SbF6 salt) species.There is also a good deal of evidence from NMR measurements demonstrating that acylium ions can exist in nonnucleophilic solvents. The 

In general, Friedel-Crafts acylation shows a preference for para over ortho substitution, although highly reactive acylating reagents such as perfluorobenzoyl chloride are an exception. 

Friedel-Crafts acylation usually involves the reaction of an acyl halide, a Lewis acid catalyst, and the aromatic reactant. Several species may function as the active electrophile, depending on the reactivity of the aromatic compound. For activated aromatics, the active electrophile can be a discrete positively charged acylium ion or a complex formed between the acyl halide and the Lewis acid catalyst. For benzene and less reactive aromatics, it is believed that the active electrophile is a protonated acylium ion or an acyiium ion complexed by a Lewis acid. Reactions using acylium salts are slow with toluene or benzene as the reactant and do not proceed with chlorobenzene. The addition of triflic acid accelerates the reactions with benzene and toluene and permits reaction with chlorobenzene. These results suggest that a protonation step must be involved. 

Acylium salts are generated at slightly higher temperatures or with more reactive acyl halides. For example, both 4-methylbenzoyl chloride and 2,4,6-trimethylbenzoyl 

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Classically, vinylsilanes have served as nucleophiles in Friedel-Crafts acylation and related reactions with strong electrophiles.4,4a 89 These strategies have been employed in the synthesis of natural products.90,9011... 

Kozhevnikov, I. V. Friedel-Crafts acylation and related reactions catalyzed by heteropoly acids. Appl. Cat. A 2003, 256, 3-18. 

Some Related Examples. A closely related problem is the rate behavior of aromatic donors in Friedel-Crafts acylation and analogous reactions. Here coordination plays a dual role. The initial Lewis acid which is added is taken up by the best donor species, frequently the substrate. Once this reaction is at equilibrium, additional amounts of Lewis acid can react with the other species present to generate the effective electrophile. The kinetic behavior of such systems was first delineated by Olivier in 1914. He studied the reactions ... 

This reaction is related to the Friedel-Crafts Acylation and Baddeley Isomerization. 

This reaction is related to the Friedel-Crafts Acylation, Reimer-Tiemann Reaction, Houben-Hoesch Acylation, and Vilsmeier-Haack Formylation. 

Friedel-Crafts acylation is related to Friedel-Crafts alkylation, with an acylium cation acting as the electrophile. However, in industrial aromatic chemistry, because of the high consumption of catalyst, this reaction is of much less importance than Friedel-Crafts alkylation. Nonetheless, it has been used, for example, in the manufacture of anthraquinone from phthalic anhydride and benzene. 

Olah, G.A. Friedel-Crafts and Related Reactions, III-Acylation and Related Reactions Intersci. Publ., New York/London/Sydney (1964)... 

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation. An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

Acyl-transfer reactions are some of the most important conversions in organic chemistry and biochemistry. Recent work has shown that adjacent cationic groups can also activate amides in acyl-transfer reactions. Friedel-Crafts acylations are known to proceed well with carboxylic acids, acid chlorides (and other halides), and acid anhydrides, but there are virtually no examples of acylations with simple amides.19 During studies related to unsaturated amides, we observed a cyclization reaction that is essentially an intramolecular acyl-transfer reaction involving an amide (eq 15). The indanone product is formed by a cyclization involving the dicationic species (40). To examine this further, the related amides 41 and 42 were studied in superacid promoted conversions (eqs 16-17). It was found that amide 42 leads to the indanone product while 41... 

For reviews of Friedel-Crafts acylation, see Olah Friedel-Crafts and Related Reactions Wiley New York, 1963-1964, as follows vol. 1, Olah, pp. 91-115 vol. 3, Gore, pp. 1-381 Peto, pp. 535-910 Sethna, pp. 911-1002 Jensen Goldman, pp. 1003-1032. For another review, see Gore Chem. Ind. (London) 1974, 727-731. 

The dicyclopentadienyl metal compounds undergo Friedel-Crafts alkylation and acylation, sulfonation, metalation, arylation, and formyla-tion in the case of ferrocene, dicyclopentadienyl ruthenium, and dicyclopentadienyl osmium, whereas the others are unstable to such reactions ( ). Competition experiments (128) gave the order of electrophilic reactivity as ferrocene > ruthenocene > osmocene and the reverse for nucleophilic substitution of the first two by n-butyl lithium. A similar rate sequence applies to the acid-catalysed cleavage of the cyclopentadienyl silicon bonds in trimethylsilylferrocene and related compounds (129), a process known to occur by electrophilic substitution for aryl-silicon bonds (130). 

For the purposes of this review, we include probe molecules that can be either directly adsorbed or formed in situ. Examples of the latter case are carbenium ions and related electrophilic species. We will also consider several important heteroatom-substituted carbenium ions and heteroatom analogs of carbenium ions. Acylium ions are the intermediates in Friedel-Crafts acylation reactions (96). The most simple, stable acylium ion is the acetylium ion, 1, and others are formally derived by replacing the methyl group with other R groups. Oxonium ions, formed by alkylation of an ether, resemble carbenium ions but are in fact onium ions in terms of their structures. Their stabilization requires strongly acidic media, and like carbenium ions, oxonium ions have been proposed as intermediates in a... 

The synthesis of a pyrrole segment common to netropsin and distamycin is shown in Scheme 2ji°l Friedel-Crafts acylation of 1-methylpyrrole (1) followed by nitration at C4 provides 3 in 54% yield. After a haloform reaction, hydrogenolysis, N-protection with B0C2O, and saponification, the pyrrolecarboxylic derivative acid 7 was obtained in 30% overall yield from 3. This monomer is readily chain-extended to the pyrrole-imidazole derivative 9 (Scheme 3)J10 Furthermore, solid-phase synthesis with this and related pyrrole-containing building blocks leads to polyamides that have recently been used in the recognition of a 16 base-pair sequence in the minor groove of DNA.1" ... 

The mechanism of the chloromethylation reaction is related to that of Friedel-Crafts alkylation and acylation and probably involves an incipient chloro-methyl cation, CH2C1 ... 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

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