By Friedel-Crafts acylation reaction

A number of commercially important fragrance molecules have been synthesized by Friedel-Crafts acylation reactions in these ionic liquids. Traseolide (5-acetyl-l,l,2,6-tetramethyl-3-isopropylindane) (Scheme 5.1-63) has been made in high yield in the ionic liquid [EMIM]C1/A1C13 (X(A1C13) = 0.67) [95]. 

The electrophile in a Friedel-Crafts acylation reaction is an acyl cation (also referred to as an acylium ion) Acyl cations are stabilized by resonance The acyl cation derived from propanoyl chloride is represented by the two resonance forms... 

PoIysuIfonyIa.tlon, The polysulfonylation route to aromatic sulfone polymers was developed independendy by Minnesota Mining and Manufacturing (3M) and by Imperial Chemical Industries (ICI) at about the same time (81). In the polymerisation step, sulfone links are formed by reaction of an aromatic sulfonyl chloride with a second aromatic ring. The reaction is similar to the Friedel-Crafts acylation reaction. The key to development of sulfonylation as a polymerisation process was the discovery that, unlike the acylation reaction which requires equimolar amounts of aluminum chloride or other strong Lewis acids, sulfonylation can be accompHshed with only catalytic amounts of certain haUdes, eg, FeCl, SbCl, and InCl. The reaction is a typical electrophilic substitution by an arylsulfonium cation (eq. 13). 

The preparation of a formyl-substituted aromatic derivative 3 from an aromatic substrate 1 by reaction with hydrogen cyanide and gaseous hydrogen chloride in the presence of a catalyst is called the Gattermann synthesis This reaction can be viewed as a special variant of the Friedel-Crafts acylation reaction. 

The synthetic importance of the Houben-Hoesch reaction is even more limited by the fact that aryl ketones are also available by application of the Friedel-Crafts acylation reaction. 

The initial series of major tranquilizers consists of alkylated derivatives of 4-aryl-4-hydroxypiperidines. Construction of this ring system is accomplished by a set of rather unusual reactions. Condensation of methylstyrenes with formaldehyde and ammonium chloride afford the corresponding hexahydro-1,3-oxazines (119). Heating these oxazines in the presence of acid leads to rearrangement with loss of water to the tetrahydropyridines. Scheme 1 shows a possible reaction pathway for these transformations. Addition of hydrogen bromide affords the expected 4-bromo compound (121). This last is easily displaced by water to lead to the desired alcohol (122) The side chain (123) is obtained by Friedel-Crafts acylation of p-fluorobenzene with 4-chloro-butyryl chloride. Alkylation of the appropriate arylpiperidinol with 123 affords the desired butyrophenone derivative. Thus,... 

Friedel-Crafts acylation reactions usually involve the interaction of an aromatic compound with an acyl halide or anhydride in the presence of a catalyst, to form a carbon-carbon bond [74, 75]. As the product of an acylation reaction is less reactive than its starting material, monoacylation usually occurs. The catalyst in the reaction is not a true catalyst, as it is often (but not always) required in stoichiometric quantities. For Friedel-Crafts acylation reactions in chloroaluminate(III) ionic liquids or molten salts, the ketone product of an acylation reaction forms a strong complex with the ionic liquid, and separation of the product from the ionic liquid can be extremely difficult. The products are usually isolated by quenching the ionic liquid in water. Current research is moving towards finding genuine catalysts for this reaction, some of which are described in this section. 

The first example of a Friedel-Crafts acylation reaction in a molten salt was carried out by Raudnitz and Laube [90]. It involved the reaction between phthalic anhydride and hydroquinone at 200 °C in NaCl/AlCl3 (X(A1C13) = 0.69) (Scheme 5.1-58). 

The Fries rearrangement can be viewed as a type of Friedel-Crafts acylation reaction. Two examples of this reaction are given in Scheme 5.1-61. The first is the rearrangement of 4,4 -diacetoxybiphenyl to 4,4 -dihydroxy-3,3 -diacetoxybiphenyl in a NaCl/AlCl3 (X(A1C13) = 0.69) molten salt [93]. The second example is the rearrangement of phenyl 3-chloropropionate to 2 -hydroxy-3-chloropropiophenone, followed by cyclization to an indanone [94]. 

The Friedel-Crafts acylation reaction has also been performed in iron(III) chloride ionic liquids, by Seddon and co-workers [96]. An example is the acetylation of benzene (Scheme 5.1-66). Ionic liquids of the type [EMIM]Cl/FeCl3 (0.50 < X(FeCl3) < 0.62) are good acylation catalysts, with the added benefit that the ketone product of the reaction can be separated from the ionic liquid by solvent extraction, provided that X(FeCl3) is in the range 0.51-0.55. 

The ability of iron(III) chloride genuinely to catalyze Friedel-Crafts acylation reactions has also been recognized by Holderich and co-workers [97]. By immobilizing the ionic liquid [BMIM]Cl/FeCl3 on a solid support, Holderich was able to acetylate mesitylene, anisole, and m-xylene with acetyl chloride in excellent yield. The performance of the iron-based ionic liquid was then compared with that of the corresponding chlorostannate(II) and chloroaluminate(III) ionic liquids. The results are given in Scheme 5.1-67 and Table 5.1-5. As can be seen, the iron catalyst gave superior results to the aluminium- or tin-based catalysts. The reactions were also carried out in the gas phase at between 200 and 300 °C. The acetylation reac-... 

Scheme 11.4 shows some other representative Friedel-Crafts acylation reactions. Entries 1 and 2 show typical Friedel-Crafts acylation reactions using A1C13. Entries 3 and 4 are similar, but include some functionality in the acylating reagents. Entry 5 involves formation of a mixed trifluoroacetic anhydride, followed by acylation in 85% H3PO4. The reaction was conducted on a kilogram scale and provides a starting material for the synthesis of tamoxifen. Entry 6 illustrates the use of bismuth triflate as... 

The important bluish mixing component 11.22 for whitening polyester is made by Friedel-Crafts acylation of pyrene (Scheme 11.17). This tetracyclic hydrocarbon is not unlike anthracene in its susceptibility to substitution reactions. The most stable bond arrangement in pyrene appears to be that shown as form 11.47a, which contains three benzenoid (b) rings. Canonical form 11.47b, containing only two such rings, contributes to a lesser extent (Scheme 11.18). In all monosubstitutions, pyrene is attacked initially at the 3-position, corresponding to the a-positions in anthracene or naphthalene. 

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],... 

The quinolizine derivative 276 was obtained through a Friedel-Crafts acylation reaction onto the C-3 indole position of 275. This precursor was obtained by a sequence comprising a Fischer cyclization leading to 5-methyl-2-(2-pyridyl)indole 274, catalytic hydrogenation, N-alkylation with ethyl bromoacetate, and hydrolysis of the ester group (Scheme 59) <1999FA479>. 

Sc(OTf)3 catalyzes Friedel-Crafts acylation reactions effectively (Scheme 12).52 While more than stoichiometric amounts of a Lewis acid such as A1C13 or BF3-OEt2 are needed because of consumption of the Lewis acid by coordination to products, a catalyic amount of Sc(OTf)3 is enough to complete the reactions. 

Friedel-Crafts acylation reactions of aromatics are promoted by Tilv complexes.104 In some cases, a catalytic amount of the titanium compound works well (Scheme 28). In addition to acyl halides or acid anhydrides, aldehydes, ketones, and acetals can serve as electrophile equivalents for this reaction.105 The formylation of aromatic substrates in the presence of TiCl4 is known as the Rieche-Gross formylation metalated aromatics or olefins are also formylated under these conditions.106... 

The presence of Lewis acidic species in chloroaluminate ionic liquids has also been used to bring about various acid catalysed transformations that do not require additional catalysts. For example, acidic ionic liquids are ideally suited to Friedel-Crafts acylation reactions. In a traditional Friedel-Crafts acylation an acylium ion is generated by reaction between acyl chloride and A1C13 or FeCL as shown in Scheme 10.7. 

Acetyl-3-bromofuran (1141) was prepared by Friedel-Crafts acylation of 3-bromofuran (1140). Wittig reaction of 1141 with methyltriphenylphosphonium bromide and butyllithium led to 3-bromo-2-propenylfuran (1142), which, on Sonogashira coupling with ethyl 2-ethynylphenylcarbamate (1143), provided N-protected (2-isopropenylfur-3-yl)ethynylaniline 1144. The TBAF-promoted... 

The electron-rich thiophene ring system can be annelated by intramolecular Friedel-Crafts acylation reactions to give fused thiophenes <99IJC648, 99JMC2774>. The synthesis of a thiophene isostere of ninhydrin involved an intramolecular Friedel-Crafts acylation <99SL1450>. Specifically, treatment of thiophene 86 with thionyl chloride followed by aluminum chloride gave annelated thiophene 87. The synthesis of isothianinhydrin 88 was then accomplished in six steps from 87. 

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... 

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