Friedel Crafts reaction para selectivity

Transfer of selectivity from the lower to the upper rim is the most useful method for the selective synthesis of partially functionalized calixarenes at the upper rim. Indeed, one can exploit the different reactivity of aryl ethers compared to phenols to introduce, regioselectively, additional functional groups at the upper rim of partially alkylated calixarenes. Moreover, if l,3-dialkoxy-/ -r rt-butylcalix[4]arenes are submitted to the reverse Friedel-Crafts reaction, the tert-hwiyX groups are detached only from the para position of the phenolic nuclei, obtaining compounds where only two diametral aromatic rings are available for further functionalization. 

In this way, selective halogenation, nitration, and Friedel-Crafts reactions are accomplished. For example, the synthesis of 2-nitrobenzenamine (o-nitroaniline) employs this strategy in conjunction with sulfonation to block the para position. 

A Friedel-Crafts-type reaction of phenols under basic conditions is also possible. Aqueous alkaline phenol-aldehyde condensation is the reaction for generating phenol-formaldehyde resin.34 The condensation of phenol with glyoxylic acid in alkaline solution by using aqueous glyoxylic acid generates 4-hydroxyphenylacetic acid. The use of tetraalkylammonium hydroxide instead of sodium hydroxide increases the para-selectivity of the condensation.35 Base-catalyzed formation of benzo[b]furano[60]- and -[70]fullerenes occurred via the reaction of C60CI6 with phenol in the presence of aqueous KOH and under nitrogen.36... 

Other Formylations. Formyl fluoride, the only known stable formic acid derivative, can be used to perform Friedel-Crafts-type acylation to form aromatic aldehydes. The method was developed by Olah and Kuhn.105 Although a number of Lewis acids may be used, BF3 is the best catalyst. It is dissolved in the aromatic compound to be formylated then formyl fluoride is introduced at low temperature and the reaction mixture is allowed to warm up to room temperature. The aldehydes of benzene, methylbenzenes, and naphthalene were isolated in 56-78% yields. Selectivities are similar to those in the Gattermann synthesis ( toiuene benzene = 34.6, 53.2% para isomer). The reacting electrophile was suggested to be the activated HCOF BF3 complex and not the free formyl cation. Clearly there is close relationship with the discussed CO—HF—BF3 system. 

The set of catalysts selected for the dehydration of 2-butanol was also tested for the Friedel-Crafts acylation of anisole [69, 70]. The catalytic test was performed in the liquid phase due to the high boiling points of the reactants and products of this reaction. Anisole was reacted with acetic anhydride at 120 °C in the absence of solvent. In principle, acylation can occur on both the ortho and para positions of anisole. The main product (>99%) over all catalysts in this study was para-methoxyacetophenone, indicating that the reaction predominantly takes place inside the zeolite micropores. The same trend in catalytic activity as in the 2-buta-nol dehydration reaction is observed the conversion of anisole into para-nicihoxy-acetophenone increases upon increasing Ge content of the catalyst (Fig. 9.17) [67]. The main cause of deactivation for this reaction is accumulation of the reaction products inside the micropores of the zeolite. The different behavior of Ge-ZSM-5, compared with ZSM-5, may therefore be due to improved diffusional properties of the former, as the presence of additional meso- and macropores allows for... 

Figure 5.33 presents Friedel-Crafts acylations, taking benzoylations of toluene (top line) and para-tert-butyl toluene (Figure 5.33, bottom) as an example. The methyl group of toluene preferentially directs the benzoyl residue into the para-position. The ortho-benzoylated toluene occurs only as a by-product. In para-tert-butyl toluene both the methyl- and the tert-butyl substituent direct the electrophile towards the ortho-position, since both para-positions are occupied and could at best react with de-ferf-butylation, i.e., in a—sterically hindered — ipso-substitution (cf. Figure 5.5). Indeed, we see reaction ortho to the methyl group and not ortho to the ferf-butyl group. This selectivity can be ascribed to minimized steric interactions in the preferred sigma complex intermediate.

Exactly the same sort of mechanism accounts for the reactions of aryl silanes with electrophiles under Friedel-Crafts conditions. Instead of the usual rules governing ortho, meta, and para substitution using the directing effects of the substituents, there is just one rule the silyl group is replaced by the electrophile at the same atom on the ring—this is known as ipso substitution. Actually, this selectivity comes from the same principles as those used for ordinary aromatic substitution (Chapter 22) the electrophile reacts to produce the most stable cation—in this case (3 to silicon. Cleavage of the weakened C-Si bond by any nucleophile leads directly to the ipso product. 

This is not a concerted rearrangement mechanism of the usual cationic sort, like the pinacol (Chapter 2), but a normal ionic reaction. The Lewis acid catalyses the breakdown of the ester 8 into an acylium ion and a metal complex of the phenol which remain associated as an ion pair 9 in non-polar solvents. This naturally tends to give the ortho product as the acylium ion is held close to the ortho position by electrostatic interactions. In polar solvents, the ion pair is separated into two independent ions which show the normal Friedel-Crafts selectivity, that is high preference for the para product. 

Pioneering and extensive work in this field was realized in 1985 [8] by use of exchanged Ce Y-zeolite as the catalyst for the Friedel-Crafts acylation of toluene (Eq. 3) and xylene with carboxylic acids. Different aspects of this initial work are of interest. Firstly, it shows that the mild acidity of zeolites is sufficient to effect the reaction, and, secondly, it shows that this reaction can be conducted with carboxylic acids and not the corresponding acid chlorides. Only the more lipophilic acids were found reactive whereas no acetylation occurs with acetic acid. The reaction with toluene (Table 1) is extremely para selective and more selective than a conventional aluminum chloride homogeneous process. The different reactivities reported in this paper are essentially because of differences between preferential adsorption of the substrates on the catalyst and not their intrinsic activity. 

Geneste and coworkers in 1986 reported that zeolites catalyzed Friedel-Crafits acylations in presence of a Ce + exchanged zeolite Y catalyzed the acylation of toluene and xylenes with carboxylic acids (Table 11.2) [42]. They also mentioned that only mild acidity is sufficient for Friedel-Crafts acylations which can be induced by means of zeolites catalysts. The reaction exhibited a very high para-selectivity. 

Chalcones (123) are commonly prepared by Claisen-Schmidt or aldol condensation. An important way to synthesize chalcones (123) is the Friedel-Crafts acylation involving treatment of acid chlorides (121) with arenes (122). Such a protocol for the synthesis of chalcones (123) was developed by More et al. (2012) using nano-ZnO heterogeneous catalyst under solvent-free conditions at room temperature (Scheme 9.38). Arenes (122) of all sorts, activated as well as unactivated, reacted smoothly to afford the chalcones (123) in excellent yield. High regioselectivity was observed during the course of reaction, which occurred selectively at the para-position of OMe, Br, Me, and Cl. 

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