Free radical attack at the ring carbon atoms

2 Free radical attack at the ring carbon atoms 

Free radical reactions are still very much less common in azole chemistry than those involving electrophilic or nucleophilic reagents. In some reactions involving free radicals, substituents have little orienting effect however, rather selective radical reactions are now known. 

Phenyl radicals attack azoles unselectively to form a mixture of phenylated products. Relative rates and partial rate factors are given in Table 8. The phenyl radicals may be prepared from the usual precursors PhN(NO)COMe, Pb(OCOPh)2, (PhC02)2 or PhI(OCOPh)2. Substituted phenyl radicals react similarly. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus, imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)24i). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(16)123) the mechanism involves an intermediate a-complex. 

Similar reactions occur with acyl radicals, for example with the CONH2 radical from formamide (74AHC(16)123 . 

The behavior of the 3-alkylidene-l-pyrazoline radical cations generated by photoinduced electron transfer was examined 2005TL261 . The nitrogen-retained radical cations were detected using laser flash photolysis. 

The photochemical products indicated that ( /Z)-isomerization, intramolecular cyclization, and solvent addition (acetonitrile) occurred. A density functional study of the radical reactions of 3-methyl-l-phenyl-2-pyrazolin-5-one was carried out 1997JPC3769 . 

Pyrazolinones are oxidized by phenoxy radicals to the corresponding radicals which, in turn, dimerize or combine with the phenoxy radical 93JPR607 . Trichloromethyl radicals react to pyrazoles to afford ring-expansion products (see Section 3.01.5.2) 89PJS377 . 

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While free radical attack in step (i) is by no means confined to carbon atom 4, the products obtained in the reactions involving the lower polyisoprenes indicate that this process is the dominant one. Likewise in step (ii) sulfur may frequently add at carbon atom 4 rather than at atom 2. Addition in the manner shown is indicated, however, by infrared spectra, which reveal the formation of —CH=CH— groups during vulcanization. The scheme accounts also for the observed constancy of the C/H ratio during vulcanization and for the relatively low efficiency of utilization of sulfur in the formation of cross-linkages in the absence of accelerators. A preponderance of the sulfur is involved in addition without formation of cross-linkages a considerable fraction of the thus-combined sulfur may occur in five- and six-membered heterocyclic rings formed by the mechanisms indicated. 

We consider as dihydro derivatives those rings which contain either one or two 5p3-hybridized carbon atoms. According to this definition, all reactions of the aromatic compounds with electrophiles, nucleophiles or free radicals involve dihydro intermediates. Such reactions with electrophiles afford Wheland intermediates which usually easily lose H+ to re-aromatize. However, nucleophilic substitution (in the absence of a leaving group such as halogen) gives an intermediate which must lose H and such intermediates often possess considerable stability. Radical attack at ring carbon affords another radical which usually reacts further rapidly. In this section we consider the reactions of isolable dihydro compounds it is obvious that much of the discussion on the aromatic heterocycles is concerned with dihydro derivatives as intermediates. 

Foods of animal origin are suspected to contain some amount of COP formed by autoxidation. Cholesterol autoxidation is a well-established free radical process that involves the same chemistry that occurs for the oxidation of unsaturated lipids. Cholesterol contains one double bond at the carbon-5 position therefore, the weakest points in its structure are at the carbon-7 and carbon-4 positions. However, due to the possible influence of the hydroxyl group at carbon-3 and the tertiary carbon atom at carbon-5, the carbon-1 position is rarely attacked by molecular oxygen, and therefore the abstraction of an allylic hydrogen predominantly occurs at carbon-7 and gives rise to a series of A and B ring oxidation products. In the chain reaction,... 

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