Friedel-Crafts reaction electron density

Beyer synthesis, 2, 474 electrolytic oxidation, 2, 325 7r-electron density calculations, 2, 316 1-electron reduction, 2, 282, 283 electrophilic halogenation, 2, 49 electrophilic substitution, 2, 49 Emmert reaction, 2, 276 food preservative, 1,411 free radical acylation, 2, 298 free radical alkylation, 2, 45, 295 free radical amidation, 2, 299 free radical arylation, 2, 295 Friedel-Crafts reactions, 2, 208 Friedlander synthesis, 2, 70, 443 fluorination, 2, 199 halogenation, 2, 40 hydrogenation, 2, 45, 284-285, 327 hydrogen-deuterium exchange, 2, 196, 286 hydroxylation, 2, 325 iodination, 2, 202, 320 ionization constants, 2, 172 IR spectra, 2, 18 lithiation, 2, 267... 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

In the case of nitrogen-containing aromatic derivatives, the basic nitrogen atom can he protected (sec. 7.3). Conversion to an amide (such as A -acetylaniline -called acetanilide, from aniline) withdraws electron density that diminishes the basicity of the amino group, allowing the Friedel Crafts reaction to give 181. 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

The study of cocatalysis in cationic polymerizations is extremely complicated by the fact that Lewis acids can participate in a variety of ill defined reactions (91). Satchell (91, 92) regards the hydrogen exchange reaction between Bronsted acids and aromatics catalyzed by Lewis acids as a prototype for Friedel-Crafts catalysis. He postulates that cocatalytic efficiency is determined by the stability of the complex anion B -f HX + SnCl4 - BH SnCl4Xe. A simple enhancement of conventional acidity by B + HX -> BH Xe as proposed by Plesch (93) and Russel (94) is considered to be unimportant. The stability of the complex and its catalytic activity are determined by the electron density... 

Iron tricarbonyl forms exceptionally stable complexes with 1,3-dienes. The complexes are uncharged, readily soluble species, chromatographable and, for the simpler versions, distillable. They are formed by direct reaction of the 1,3-diene with Fe(CO)5, Fc2(CO)9, or Fe3(CO)i2. These iron diene complexes are known to be reactive toward electrophiles, undergoing the analogous reaction to electrophilic aromatic substitution under Friedel-Crafts conditions. However, it is clear that the metal-ligand unit increases the polarizibility of the diene unit, and, with a sufficiently reactive nucleophile, can provide a sink for electron density. How reactive does the nucleophile need to be The other important selectivity question for 1,3-dienes concerns the regioselectivity. 

We have seen that the intramolecular version of the Friedel-Crafts acylation reaction is wide-ranging and that reaction conditions can normally be devised to allow the synthesis of a large number of different ring sizes. Cyclizations can also be carried out when the aryl residues have widely differing electron densities. The reaction is subject to fewer anomalies than is the case with the inteimolecular version. There have been examples reported where unexpected products have been obtained, but a careful choice of reaction conditions will normally allow these problems to be avoided. To quote just one example, cinna-moyl chloride (the trans isomer) would not be expected to give a cyclized product, and a reaction with toluene using aluminum chloride as the catalyst leads to the expected inteimolecular reaction product. A reaction carried out in benzene solution, however, gave rise to a mixture of 3-phenylindan-l-one and 1,3,3-triphenylpropanone. 

It should be noted, however, that the lack of electron density in the 7t-system may be bypassed by creating local (T-electron density by lithiation and reaction with suitable electrophiles. Quenching of lithiated alkoxy-l,2,3-triazines with aromatic aldehydes generates (a-hydroxybenzyl)-l,2,3-triazines, products of an electrophilic attack on carbon. Dehydrogenation of their alcohol function with manganese dioxide affords formal Friedel-Crafts acylation products <1998MI119>. Lithiation has been discussed from a theoretical point of view in Section 9.01.2.13, and practical implications are presented in Section 9.01.5.5. 

Even though the electron density of the diene system in tricarbonyl(T -diene)iron complexes is reduced due to 7t-donation to the iron center, reactions with various electrophiles are still possible. Thus, Friedel-Crafts alkylation of (diene)iron complexes with alkoxychloromethanes gives selectively cis- or tra s-(alkoxypenta-2,4-diene)iron complexes depending on the work-up conditions (Scheme 4—110). ... 

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