Pyridine phenylation, radical

The results are consistent with the rate-determining step being addition of the aryl radical to the aromatic ring, Eq. (9). Support for this mechanism is derived from the results of three other studies (a) When A -nitrosoacetanilide is decomposed in pyridine, the benzene formed by abstraction of hydrogen from pyridine by phenyl radical accounts for only 1 part in 120 of the reaction leading to phenyl-pyridines. (b) 9,9, 10,lCK-Tetrahydro-10,10 -diphenyl-9,9 -bianthryl is formed in the reaction between phenyl radicals and anthracene, probably by the addition mechanism in Eq. (11). Adducts are also formed in the reactions of benzyl radicals with anthracene- and acridine. ... 

The quantitative phenylation of pyridine has been studied by two groups of workers. Dannley and Gregg showed that 2-, 3-, and 4-phenylpyridine are formed in relative amounts 58 28 14 in the phenylation of pyridine with dibenzoyl peroxide, as estimated by infrared spectrophotometry. Hey and his co-workers obtained the ratios shown in Table I for the phenylation of pyridine using four different sources of phenyl radicals. ... 

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

In many cases, however, the ortho isomer is the predominant product, and it is the meta para ratio which is close to the statistical value, in reactions both on benzenoid compounds and on pyri-dine. " There has been no satisfactory explanation of this feature of the reaction. One theory, which lacks verification, is that the radical first forms a complex with the aromatic compound at the position of greatest electron density that this is invariably cither the substituent or the position ortho to the substituent, depending on whether the substituent is electron-attracting or -releasing and that when the preliminary complex collapses to the tr-complex, the new bond is most likely to be formed at the ortho position.For heterocyclic compounds such as pyridine it is possible that the phenyl radical complexes with the nitrogen atom and that a simple electronic reorganization forms the tj-complex at the 2-position. 

Qualitatively, the results shown in Tables IV and V indicate that the methyl radical, just as the phenyl radical, substitutes pyridine preferentially in the 2- and 4-positions. The absence of the 3-isomer in these reactions is probably a result of the method of analysis... 

It is difficult to treat the effect of a heteroatom on the localization energies of aromatic systems, but Brown has derived molecular orbital parameters from which he has shown that the rates of attack of the phenyl radical at the three positions of pyridine relatively to benzene agree within 10% with the experimental results. He and his co-workers have shown that the formation of 1-bromoisoquinoline on free-radical bromination of isoquinoline is in agreement with predictions from localization energies for physically reasonable values of the Coulomb parameters, but the observed orientation of the phcnylation of quinoline cannot be correlated with localization ener-... 

Free radical substitution of pyridines usually occurs principally at position 2 (Table 25), which is in agreement with theoretical calculations (69CCC1110). 2-Substitution is more favored in methylation than in phenylation of pyridine. This suggests that the methyl has more nucleophilic character than the phenyl radical. Furthermore, methylation of pyridine in acidic solution gives 13-fold excess of 2- over 4-substitution, although the overall yield is low. Alkyl and aryl radicals have been generated from diverse sources (Table 25). 

In sharp contrast, homolytic arylation is unselective and gives low yields. Phenyl radicals attack pyridine unselectively to form a mixture of 2-, 3- and 4-phenylpyridines in proportions of ca. 53, 33 and 14%, respectively. The phenyl radicals may be prepared from the normal precursors PhN(NO)COMe, Pb(OCOPh)4, (PhC02)2 or PhI(OCOPh)2. Substituted phenyl radicals react similarly. 

Photolysis of aryl or pyridyl oxime esters in pyridine provides a-phenylpyridines as the major products together with bipyridyls (84TL3887). Rate constants for the addition of phenyl radical to protonated and non-protonated 4-substituted pyridines have been determined by studing the competition between phenyl radical addition and chlorine abstraction from carbon. The 4-arylpyridines were the major products, and no 3-substituted pyridines were observed. Among the solvents studied (MeCN, DMF, DMSO, and HMPA), MeCN gave the highest yields and selectivity (910PP438). 

Indirect support for this hypothesis has now been obtained. Phenyla-tion of 3-cyclohexyl pyridine with phenyllithium gave a 2,3-/2,5-isomer ratio of 65 35.2460 The cyclohexyl radical is expected to be at least as bulky as a phenyl radical. The exclusive formation of the 2,3-isomer in the reaction of phenyllithium both with 3-amino- and 3-methoxy-pyridine has been attributed to the formation of a complex such as 111 between the lone-pair of electrons on the 3-substituent and the lithium atom, in which the phenyl group would be suitably... 

Goldschmidt and Beer.372 The 2-alkylated product is the main one formed. This orientation is not unexpected since, compared with the phenyl radical, an alkyl radical should have some nucleophilic character. The j8-/y- ratio is also lower than in the phenylation, as expected for a more nucleophilic radical.371 Pyridine has a methyl affinity of 3 compared with benzene.373 This, however, does not represent the relative amount of picolines and toluene formed with acetyl peroxide.371... 

The homolytic arylation of pyridine has been studied somewhat more systematically but by no means exhaustively. Quantitative analysis of the phenylation products using various sources of phenyl radicals has been achieved by ultraviolet spectroscopic or gas chromatographic methods. The results of some recent determinations are given in Table XV. 

The effects of substituents upon the orientation of the entering phenyl radical and upon the reactivity of the pyridine nucleus have not received much attention. 4-Picoline is substituted by the 3-pyridyl radical (from the Gomberg-Hey reaction) to give a mixture containing 15% of the product of attack at the a-position (163) and 55% of product of attack at the /3-position (164). A very similar result was... 

The free-radical arylation of pyridine N-oxides has not been studied systematically, alkylation not at all. When pyridine A-oxide was treated with benzene- and p-chlorobenzenediazonium salts only the 2-arylpyridine jV-oxides were isolated.393 No mention was made of the formation of the 3- and 4-aryl derivatives expected to be produced as well. The phenylation of pyridine N-oxide (diazoaminobenzene at 131° or 181° was found to be the most convenient source of phenyl radicals) was reinvestigated,394 and the reactivities of the nuclear positions found to be in the order 2 > 4 > 3, which is also that predicted6 on the basis of atom localization energy calculations. 2-Phenyl-pyridine N-oxide formed 71-81% of the total phenylation products, whereas the 3-isomer comprised only 5.6-9.6% of that total. The phenylpyridines were found among the by-products of the reaction. 

In protonated pyridine series, a transition state similar to a charge-transfer complex (27) would allow the clear distinguishing even of carbon free radicals differing little in nucleophilicity, such as methyl, cyclopropyl and phenyl radicals. 

In regard to the reactions of cation radicals with stable radicals, such as l,l-diphenyl-2-picrylhydrazyl, and with well-known spin traps, virtually nothing can be found in the literature. The pyridine cation radical has been reported to add to the spin trap phenyl-N-tert-butyl nitrone (37). 

Pyridine cation radical was identified as a reaction intermediate by spin trapping with phenyl-N-t-butyl nitrone (142). The very stable... 

The first report of the photochemistry of a conjugated aromatic sulfoxide appears to be that of Kharasch and Khodair [32]. In a study more principally aimed at the sulfones, they showed that photolysis of diphenyl sulfoxide 5-H in benzene led to biphenyl 41 (53%), diphenyl sulfide (7%), and trace diphenyl-disulfide 45. Biphenyl was also the major product of diphenyl sulfone photolysis, and it was shown to arise from attack of the photochemically generated phenyl radical on solvent (benzene). The same mechanism was clearly implied for the sulfoxide. The disulfide presumably comes from secondary photolysis of the unobserved phenyl benzenesulfenate 42. (The formation of the sulfide is addressed below in the section of deoxygenation.) Later workers showed that pyridine could be tolylated by photolysis of di-p-tolyl sulfoxide 5-Me with a product distribution quite consistent with other radical phenylations [33]. 

Derivatives of pyridine, quinoline or woqiiinolme may be prepared by causing the diazotised ammo-compounds of such substances to react with antimonites or the corresponding free acids. The parent material may contain substituents, e.g. hydroxy-, ammo-, carboxy- or phenyl- radicals or halogens. The most advantageous proportions appear to be 2 to 3 molecular equivalents of antimomte to each equivalent of heterocyclic compound. Reduction with suitable agents produces stibino-compoimds. ... 

As shown, 5-exo-trig cyclisation proceeds smoothly following Beckwith s conditions for the corresponding phenyl substrates (85T3925), demonstrating that pyridyl radicals undergo addition to unsaturated bonds in a similar fashion to phenyl radicals. In a very different type of reaction, Harrowven synthesised thieno(2,3-li)pyridines lla-c from ketenedithioacetals via the 2-pyridyl radical precursor 10 (95TL2861) (Scheme 3). 

Scheme 42 Reactions of pyridine and pyridine iV-oxide with phenyl radical...

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