Mechanisms Friedel-Crafts acylation

The acyl cation reacts with benzene by a Friedel-Crafts acylation mechanism. 

Whilst the Friedel-Crafts acylation mechanism remains to be accurately determined (ref. 6) it is reasonable to postulate four stages. 

The mechanism for that step is closely related to that of the Friedel-Crafts acylation. Upon subsequent hydrolysis the o-substituted Lewis acid-coordinated phenolate 7 is converted to the free o-acylphenol 2. By an analogous route, involving an electrophilic aromatic substitution para to the phenolate oxygen, the corresponding para-acylphenol is formed. 

Figure 16.9 Mechanism of the Friedel-Crafts acylation reaction. The electrophile is a resonance-stabilized acyl cation, whose electrostatic potential map indicates that carbon is the most positive atom (blue).

The mechanism of Friedel-Crafts acylation is not completely understood, but at least two mechanisms probably operate, depending on conditions. In most cases the attacking species is the acyl cation, either free or as an ion pair, formed by ° ... 

Whereas pyrroles normally undergo substitution at the C-2 position, 1-arylsulfonylpyrroles display a tunable reactivity in Friedel-Crafts acylations, wherein substitution occurs at C-3 in the presence of "hard acids" such as aluminum chloride but mainly at C-2 when catalyzed by weaker acids <81TL4899,81TL4901>. An alternative route to 3-aroylpyrroles 38 has been introduced via irradiation of 1-acetyl- or 1-phenylsulfonylpyrrole (36) with arenethiocarboxamides <96H(43)463>. The proposed mechanism involves formation and scission of a thietane intermediate 37, followed by hydrolysis of the resultant imine. 

The large scale preparation of the drug candidate 2 was accomplished via the Sugasawa reaction (an ortho-selective Friedel-Craft acylation on anilines) and the asymmetric addition to ketimines. Understanding the reaction mechanism and reaction parameters is the only way to gain confidence that the reactions will perform as required upon scale up. Below we discuss both subjects in detail. 

In 1978, Sugasawa et al., at Shionogi Pharmaceutical Co. reported ortho-selective Friedel-Craft acylation with free anilines with nitrile derivatives [4]. Sugasawa reported that the reaction requires two different Lewis acids (BC13 and A1C13) and does not proceed when N,N-dialkyl anilines are used. He proposed that boron bridging between nitriles and anilines led to exclusive ortho-acylation but a conclusive mechanism was not elucidated. The report did not offer any reason why two different Lewis acids were required and why the reaction did not progress with N,N-dialkyl anilines. Therefore, we initiated mechanistic studies. 

The heat of decomposition (238.4 kJ/mol, 3.92 kJ/g) has been calculated to give an adiabatic product temperature of 2150°C accompanied by a 24-fold pressure increase in a closed vessel [9], Dining research into the Friedel-Crafts acylation reaction of aromatic compounds (components unspecified) in nitrobenzene as solvent, it was decided to use nitromethane in place of nitrobenzene because of the lower toxicity of the former. However, because of the lower boiling point of nitromethane (101°C, against 210°C for nitrobenzene), the reactions were run in an autoclave so that the same maximum reaction temperature of 155°C could be used, but at a maximum pressure of 10 bar. The reaction mixture was heated to 150°C and maintained there for 10 minutes, when a rapidly accelerating increase in temperature was noticed, and at 160°C the lid of the autoclave was blown off as decomposition accelerated to explosion [10], Impurities present in the commercial solvent are listed, and a recommended purification procedure is described [11]. The thermal decomposition of nitromethane under supercritical conditions has been studied [12], The effects of very high pressure and of temperature on the physical properties, chemical reactivity and thermal decomposition of nitromethane have been studied, and a mechanism for the bimolecular decomposition (to ammonium formate and water) identified [13], Solid nitromethane apparently has different susceptibility to detonation according to the orientation of the crystal, a theoretical model is advanced [14], Nitromethane actually finds employment as an explosive [15],... 

In-situ IR-spectroscopic characterization of the Friedel-Crafts acylation of benzene in ionic liquids derived from AICI3 and FeCl3 showed that the mechanism of the reaction in ionic liquids was the same as that in 1,2-dichloroethane (128). The immobilization of ferric chloride-containing ionic liquid onto solid supports (e.g., silica and carbon) however failed to catalyze the acylation reaction, because leaching was a serious problem. When the reaction was carried out with gas-phase reactants, catalyst deactivation was observed. 

The mechanism of the Friedel-Crafts acylation reaction, formulated below for reactions using acid chlorides, probably involves the acylium ion (2) as the reactive electrophilic species, although an electrophilic complex (1) between the acid chloride and aluminium chloride may also be involved. 

The mechanism of the Friedel-Crafts acylation is the same as the Friedel-Crafts alkylation. It involves an acylium ion instead of a carbocation. Like Friedel-Crafts alkylation, a Lewis acid is needed to generate the acylium ion (R-C = 0) but unlike a carbocation the acylium ion does not rearrange since there is resonance stabilisation from the oxygen ... 

The reaction presented in this problem is known as a Friedel-Crafts acylation. Technically, this example belongs to a class of reactions referred to as electrophilic aromatic substitutions. Furthermore, the actual mechanism associated with this reaction, utilizing Lewis acid reagents as catalysts, proceeds through initial formation of an electrophilic acyl cation followed by reaction with an aromatic ring acting as a nucleophile. This mechanism, shown below, reflects distinct parallels to standard addition-elimination reaction mechanisms warranting introduction at this time. 

Please note that while the Friedel-Crafts acylation reaction is presented in discussions of addition-elimination reaction mechanisms, this reaction is actually an electrophilic aromatic substitution reaction. The correct mechanisms for a Freidel-Crafts acylation was presented in the solution for Problem 6 (h) from Chapter 7. 

Mechanism 17-5 Friedel-Crafts Alkylation 778 17-11 The Friedel-Crafts Acylation 781... 

Mechanism 17-6 Friedel-Crafts Acylation 782 Summary Comparison of Friedel-Crafts Alkylation and Acylation 784... 

The mechanism of Friedel-Crafts acylation (shown next) resembles that for alkylation, except that the electrophile is a resonance-stabilized acylium ion. The acylium ion reacts with benzene or an activated benzene derivative via an electrophilic aromatic substitution to form an acylbenzene. 

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