Substitution reactions Friedel-Crafts alkylation

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

The alkylation of pyridine [110-86-1] takes place through nucleophiUc or homolytic substitution because the TT-electron-deficient pyridine nucleus does not allow electrophiUc substitution, eg, Friedel-Crafts alkylation. NucleophiUc substitution, which occurs with alkah or alkaline metal compounds, and free-radical processes are not attractive for commercial appHcations. Commercially, catalytic alkylation processes via homolytic substitution of pyridine rings are important. The catalysts effective for this reaction include boron phosphate, alumina, siHca—alurnina, and Raney nickel (122). 

We still have to make the pyrrole with the alkyl side chain for this acylation reaction. Friedel-Crafts alkylation is not an option but pyrroles are reactive enough to do the Mannich reaction. Formaldehyde and an amine combine to give another iminium salt 107 that reacts with A-methyl pyrrole to give, after rearomatisation 109 the substituted pyrrole 110. 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

Of the many methods which have been published so far for the substitution of existing crowns, probably the most straightforward are Friedel-Crafts alkylation or acylation reactions. Cygan, Biernat and Chadzynski have reported the successful di-t-butylation of dibenzo-24-crown-8 using t-butanol as alkylating agent s . The crown was heated at 100° for 4 h in the presence of excess t-butanol and 85% phosphoric acid. The product was obtained as a crystalline (mp 52—74°) solid in 93% yield. The alkylated crowns are presumably a mixture of isomers substituted once in each ring as illustrated in Eq. (3.14). 

Blasius and coworkers have offered a somewhat different approach to systems of this general type. In the first of these, shown in Eq. (6.20), he utilizes a hydroxymethyl-substituted 15-crown-5 residue as the nucleophile. This essentially similar to the Mon-tanari method. The second approach is a variant also, but more different in the sense that covalent bond formation is effected by a Friedel-Crafts alkylation. In the reaction... 

The synthesis of an alkylated aromatic compound 3 by reaction of an aromatic substrate 1 with an alkyl halide 2, catalyzed by a Lewis acid, is called the Friedel-Crafts alkylation This method is closely related to the Friedel-Crafts acylation. Instead of the alkyl halide, an alcohol or alkene can be used as reactant for the aromatic substrate under Friedel-Crafts conditions. The general principle is the intermediate formation of a carbenium ion species, which is capable of reacting as the electrophile in an electrophilic aromatic substitution reaction. 

Mohanty et al. were the first to introduce pendent r-butyl groups in die polymer backbones. The resulting material was quite soluble in aprotic dipolar solvents.83 The PEEK precursors were prepared under a mild reaction condition at 170°C. The polymer precursor can be converted to PEEK in die presence of Lewis acid catalyst A1C13 via a retro Friedel-Crafts alkylation. Approximately 50% of die rerr-butyl substitutes were removed due to die insolubility of the product in die solvent used. Later, Risse et al. showed diat complete cleavage of f< rf-butyl substitutes could be achieved using a strong Lewis acid CF3SO3H as both die catalyst and the reaction medium (Scheme 6.15).84... 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

Friedel-Crafts alkylations are among the most important reactions in organic synthesis. Solid acid catalysts have advantages in ease of product recovery, reduced waste streams, and reduction in corrosion and toxicity. In the past, people have used (pillared) clays (18), heteropolyacids (19) and zeohtes (20) for Friedel-Craft alkylations, with mixed success. Problems included poor catalyst stabihty and low activity. Benzylation of benzene using benzyl chloride is interesting for the preparation of substitutes of polychlorobenzene in the apphcation of dielectrics. The performance of Si-TUD-1 with different heteroatoms (Fe, Ga, Sn and Ti) was evaluated, and different levels of Fe inside Si-TUD-1 (denoted Fei, Fe2, Fes and Feio) were evaluated (21). The synthesis procedure of these materials was described in detail elsewhere (22). 

The Friedel-Crafts alkylation reaction does not proceed successfully with aromatic reactants having EWG substituents. Another limitation is that each alkyl group that is introduced increases the reactivity of the ring toward further substitution, so polyalkylation can be a problem. Polyalkylation can be minimized by using the aromatic... 

The same group [38] also developed a double Heck reaction which was then terminated by a Friedel-Crafts alkylation to give 6/1-54 from 6/1-53 (Scheme 6/1.12) this involved an attack of an alkylpalladium(II) intermediate on an aryl or heteroaryl moiety. Noteworthy is the finding that the formal Friedel-Crafts alkylation occurs on both electron-rich and electron-poor heteroaromatic rings, as well as on substituted phenyl rings. Single Heck/Friedel-Crafts alkylation combinations have also been performed. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

However, one of the most common mechanisms is undoubtedly proton transfer but whereas in alkene polymerizations this reaction leaves a terminal double bond, in arylene polymerizations these are generally not found. Instead the terminal group is usually a substituted indane formed by an internal Friedel-Crafts alkylation [8, 21, 23], e.g., for a-methyl styrene ... 

To be really satisfactory, a Friedel-Crafts alkylation requires one relatively stable secondary or tertiary carbocation to be formed from the alkyl halide by interaction with the Lewis acid, i.e. cases where there is not going to be any chance of rearrangement. Note also that we are unable to generate carboca-tions from an aryl halide - aryl cations (also vinyl cations, see Section 8.1.3) are unfavourable - so that we cannot nse the Friedel-Crafts reaction to join aromatic gronps. There is also one further difficulty, as we shall see below. This is the fact that introduction of an alkyl substitnent on to an aromatic ring activates the ring towards fnrther electrophilic substitution. The result is that the initial product from Friedel-Crafts alkylations is more reactive than the... 

A similar problem of complex formation may be encountered if either amino or phenol groups are present in the substrate, and the reaction may fail. Under such circumstances, these groups need to be blocked (protected) by making a suitable derivative. Nevertheless, Friedel-Crafts acylations tend to work very well and with good yields, uncomplicated by multiple acylations, since the acyl group introduced deactivates the ring towards further electrophilic substitution. This contrasts with Friedel-Crafts alkylations, where the alkyl substituents introduced activate the ring towards further substitution (see Section 8.4.3). 

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

Despite the use of new catalys.s for manufacturing some industrial organic chemicals, many well-known classical reactions still abound. The Friedel-Crafts alkylation is one of the first reactions studied in electrophilic aromatic substitution. It is used on a large scale for making ethylbenzene. 

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