Friedel-Crafts acylation procedure

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

The various methods for introducing a formyl group (—COH) into a phenolic nucleus are discussed in Section 6.10.1, p. 990. The formation of phenolic ketones (e.g. HO-C6H4-COR) by the standard Friedel-Crafts acylation procedure (i.e. the reaction of a phenol with an acid chloride in the presence of aluminium chloride) does not always give acceptable yields except in the case of polyhydroxyphenols (p. 1006). The preferred method is to convert the phenol into the phenyl ester and to subject this to rearrangement (the Fries reaction) in the presence of aluminium chloride. 

Because acylation of an aromatic ring can be accomplished without rearrangement it is frequently used as the first step m a procedure for the alkylation of aromatic compounds by acylation-reduction As we saw m Section 12 6 Friedel-Crafts alkylation of ben zene with primary alkyl halides normally yields products having rearranged alkyl groups as substituents When a compound of the type ArCH2R is desired a two step sequence IS used m which the first step is a Friedel-Crafts acylation... 

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. 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

Many organic chemical transformations have been carried out in ionic liquids hydrogenation [4, 5], oxidation [6], epoxidation [7], and hydroformylation [8] reactions, for example. In addition to these processes, numerous synthetic routes involve a carbon-carbon (C-C) bond-forming step. As a result, many C-C bondforming procedures have been studied in ambient-temperature ionic liquids. Among those reported are the Friedel-Crafts acylation [9] and allcylation [10] reactions, allylation reactions [11, 12], the Diels-Alder reaction [13], the Heck reaction [14], and the Suzuld [15] and Trost-Tsuji coupling [16] reactions. 

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.51 In general, para attack predominates for... 

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],... 

Benzophenones are usually attached as a complete photophore. Apart from the standard chemical techniques, new C-C coupling procedures extend the synthetic repertoire. However, in some cases direct benzoylation (e.g., Friedel-Crafts acylation) of aromatic or heteroaromatic rings can provide an easy access to BP or BP-like photophores (Scheme 4D) [38,39]. 

Figure 7-11 shows a Friedel-Crafts acylation reaction. The reaction produces an aryl ketone, which is useful in synthesis because it makes it relatively easy to convert the ketone (RCOR) group to an alkyl (R) group. The procedure involves the catalytic hydrogenation of the aryl ketone, and it s particularly useful when the electrophile in a Friedel-Crafts alkylation is susceptible to rearrangement. 

A ketone can also be formed with a Friedel-Crafts acylation. The process requires an acid chloride and an aromatic compound. An aldehyde can t be formed by this procedure because the appropriate acid chloride, formyl chloride (HCOCl), is unstable and decomposes to carbon monoxide and hydrogen chloride. Figure 10-12 illustrates the preparation of acetophenone from benzene and acetyl chloride. 

Regioselectivity in Friedel-Crafts acylations can be quite sensitive to the reaction solvent and other procedural variables.45 In general, para attack predominates for alkylbenzenes.46 The percentage of ortho attack increases with the electrophilicity of the acylium ion, and as much as 50% ortho product is observed with the formylium and... 

Molten sodium tetrachloroaluminate (a 1 1 mixture of NaCl and AICI3) is a good reaction medium for the Friedel-Crafts acylation reaction given in fig. 3.3 (Wade et al., 1979). Whereas the classical procedure for the synthesis of 1-indane from 3-phenylpropanoic acid consists of three reaction steps with a total reaction time of ca. six hours (Gattermann et al., 1982), the molten salt reaction is finished in five minutes and gives an even better yield (Wade et al., 1979). 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

The sequence of addition of the reagents also affect Friedel-Crafts acylations. The most satisfactory procedure, which is actually the same what Friedel and Crafts originally used, is the addition of the catalyst as the last reactant. Another possibility also used very often is the Perrier method. It involves the prior preparation of the complex in a solvent followed by the addition of the aromatic reagent. 

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

Dibenzothiophene derivatives are available from benzo[Z> jthiophenes by this procedure. In this case the major product of Friedel-Crafts acylation is the 3-substituted derivative cf. Chapter 3.14) and reaction of succinic anhydride gives as the major product the keto acid (319), which is then reduced and cyclized via the acid chloride to 4-keto-l,2,3,4-tetrahydrodibenzothiophene (320). Better yields were obtained when 3-methoxycar-bonylpropionyl chloride was substituted for succinic anhydride in the first step (69JHC771). 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

Typical Procedure for RE(OTf)3-catalyzed Friedel-Crafts Acylation... 

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