Homolytic aromatic substitutions

An interesting method for the substitution of a hydrogen atom in rr-electron deficient heterocycles was reported some years ago, in the possibility of homolytic aromatic displacement (74AHC(16)123). The nucleophilic character of radicals and the important role of polar factors in this type of substitution are the essentials for a successful reaction with six-membered nitrogen heterocycles in general. No paper has yet been published describing homolytic substitution reactions of pteridines with nucleophilic radicals such as alkyl, carbamoyl, a-oxyalkyl and a-A-alkyl radicals or with amino radical cations. 

Mechanistically there is ample evidence that the Balz-Schiemann reaction is heterolytic. This is shown by arylation trapping experiments. The added arene substrates are found to be arylated in isomer ratios which are typical for an electrophilic aromatic substitution by the aryl cation and not for a homolytic substitution by the aryl radical (Makarova et al., 1958). Swain and Rogers (1975) showed that the reaction takes place in the ion pair with the tetrafluoroborate, and not, as one might imagine, with a fluoride ion originating from the dissociation of the tetrafluoroborate into boron trifluoride and fluoride ions. This is demonstrated by the insensitivity of the ratio of products ArF/ArCl in methylene chloride solution at 25 °C to excess BF3 concentration. 

However, these mechanistic investigations show only that the reagent in the arylation proper is an aryl radical. They say nothing about the formation of this aryl radical and the homolytic substitution of an aromatic hydrogen. Experimental research on this problem started with work of Huisgen (1951). We discussed part of... 

We might well expect the resultant phenoxy radical to attack— through the unpaired electron on its O, or on its o- or p-C, atom—a further molecule of phenol or phenoxide anion. Such homolytic substitution on a non-radical aromatic substrate has been observed where the overall reaction is intramolecular (all within the single molecule of a complex phenol), but it is usually found to involve dimerisation (coupling) through attack on another phenoxy radical ... 

In the last ten years arylation has been tbe most studied homolytic aromatic substitution, also in the heteroaromatic series. Numerous data concerning a large variety of heterocycles have permitted the definition of many details for the individual substrates, without adding, however, anything particularly new as regards the general characteristics of the reaction, already outlined in the previous review of Norman and Radda. These characteristics are substantially the same as those observed in the homocyclic aromatic series, for which comprehensive reviews are available. There is therefore a sharp difference in behavior between arylation and other homolytic substitutions described in the previous sections. These latter have quite different characteristics, and sometimes they are not known, in the homocyclic series. 

This awareness in a short time led to new homolytic aromatic substitutions, characterized by high selectivity and versatility. Further developments along these lines can be expected, especially as regards reactions of nucleophilic radicals with protonated heteroaromatic bases, owing to the intrinsic interest of these reactions and to the fact that classical direct ionic substitution (electrophilic and nucleophilic) has several limitations in this class of compound and does not always offer alternative synthetic solutions. Homolytic substitution in heterocyclic compounds can no longer be considered the Cinderella of substitution reactions. 

Homolytic substitution of thiophene as well as homolytic aromatic substitutions by thienyl radicals has been reviewed (73IJS295). In addition to this, a wider review on homolytic substitution of heteroaromatic compounds (74AHC(16)123) also briefly covers work done in the area of thiophenes. 

Homolytic liquid-phase processes are generally well suited to the synthesis of carboxylic acids, viz. acetic, benzoic or terephthalic acids which are resistant to further oxidation. These processes operate at high temperature (150-250°C) and generally use soluble cobalt or manganese salts as the main catalyst components. High conversions and selectivities are usually obtained with methyl-substituted aromatic hydrocarbons such as toluene and xylenes.95,96 The cobalt-catalyzed oxidation of cyclohexane by air to a cyclohexanol-cyclohexanone mixture is a very important industrial process since these products are intermediates in the manufacture of adipic acid (for nylon 6,6) and caprolactam (nylon 6). However, the conversion is limited to ca. 10% in order to prevent consecutive oxidations, with roughly 70% selectivity.97... 

Aromatic heterocycles may, of course, give rise to tr-radicals, e.g., 2-pyridyl (14). This review does not treat of these except incidentally where there is ambiguity as to whether a radical is a or n in character, or where a tr-radical occurs unexpectedly. Equally, transient radical adducts arising in homolytic substitution reactions which may contain a heteroaromatic moiety are not systematically considered. These have been discussed already in this Series.6... 

Hey and Grieve [125] found in 1934 that the nitro group activates the aromatic ring towards homolytic substitution. For example, the competitive phenylation of toluene and nitrobenzene by phenyl radicals showed that the yield of nitrodiphenyls was about four times greater than the yield of methyldiphenyls. 

The partial rate factors and the isomer distribution in the amination by di-methylamino radical cation of toluene, isopropylbenzene, -butylbenzene, biphenyl and naphtalene are reported in Table 7. These partial rate factors are far the highest ever observed in homolytic substitutions so that the general character of the homolytic amination allows a more relevant analogy to be drawn with the electrophilic substitutions than with the homol5rtic arylation, the only homol5rtic substitution for which numerous and accurate quantitative data exist in homo-cyclic aromatic series. 

The fact that the electrophilic alkylation, which is very important in the homocyclic aromatic series is not applicable with the heteroaromatic bases and in any case would cause a completely different orientation also contributes to the S3uithetic interest of the homolytic alkylation. Moreover, the homolytic substitution occurs without rearrangement even in the case of the neopentyl radical and without isomerization of the reaction products, which take place frequently in electrophilic alkylation. 

The first example of an intramolecular homolytic aromatic substitution was published by Pschorr more than a century ago [34], Biaryls were prepared by intramolecular homolytic substitution of arenes by aryl radicals which were generated by treatment of arenediazonium salts with copper(I) ions (Pschorr reaction). Later it has been shown that similar reactions can be conducted under basic conditions or by photochemical or thermal decomposition of the diazonium salts [35]. Electrochemical reduction [36], titanium (III) ions [37], Fe(II)-salts [38], tetrathiafulvalene... 

S02-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the A-(o-bromophenyl)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using BusSnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [77]. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-... 

In contrast to this the mechanism of the homolytic substitution of aromatic compounds is by no means clear. This can be demonstrated by two examples. In Walling s book Free Radicals in Solution published in 1957, three different mechanisms for the phenylation of benzene by benzoyl peroxide are discussed (pages 482-487), no definite differentiation based on direct experimental evidence being possible at that time. On the other hand, it was only in 1958, that new products in addition to biphenyl were identified for the decomposition of benzoyl peroxide in benzene solution when DeTar and Long (1958) isolated l, 4, l ,4"-tetrahydro-p-quaterphenyl (8) and 1,4-dihydrobiphenyl (9). 

Full details (see Vol. 1, p. 185) of the Japanese work on the preparation of trifluoromethylarenes from trifluoroiodomethane and iodoarenes in the presence of copper powder and a dipolar aprotic solvent have become available, and it appears that the best solvent in some cases is pyridine. This method (but with DMF as solvent) has also been used to prepare the compounds PhR [R = Me03C (CF3)3, CF3 0 (CF2)2, or perfluoro-2-tetra-hydrofurfuryl] in good yields from iodobenzene and the corresponding polyfluoroiodo-compounds. Perfluoroalkyl-copper compounds are very probably involved in such reactions, and the reactions of preformed n-perfluoroheptylcopper in dimethyl sulphoxide with the aromatic carbon-hydrogen bonds of benzene, toluene, p-xylene, nitrobenzene, and chlorobenzene also lead to (perfluoroalkyl)arenes (some replacement of chlorine occurs in the case of chlorobenzene). Homolytic substitution by perfluoro-heptyl radicals, perhaps within the co-ordination sphere of the copper atom,... 

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