Pyridines homolytic

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). 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

Den Hertog and Overhoff - observed that when pyridine in sulfuric acid is added to molten potassium sodium nitrate the 3-nitro derivative is formed at 300°C, whereas at 450°C 2-nitropyridme is the main product. The latter is probably a free-radical process. Schorigin and Toptschiew obtained 7-nitroquinoline by the action of nitrogen peroxide on quinoline at 100°C, possibly through the homolytic addition of NOa. Laville and Waters reported that during the decomposition of pernitrous acid in aqueous acetic acid, quinoline is nitrated in the 6- and 7-positions. They considered that the reaction proceeds as shown in Scheme 3. 

In another investigation (Loewenschuss et al., 1976) dediazoniation was studied in TFE and in acetonitrile in the presence of pyridine. There is UV and NMR evidence for the formation of a diazopyridinium cation in addition, -CIDNP absorption and emission signals were observed. Systems containing diazonium salts and pyridine are important in industrial chemistry, as pyridine is used as a proton acceptor in the diazo coupling reaction (see Sec. 12.8) in a considerable number of syntheses of azo dyes. At the same time pyridine has an unfavorable effect on the yield because of the competing homolytic dediazoniation. 

Homolytic aromatic substitution often requires high temperatures, high concentrations of initiator, long reaction times and typically occurs in moderate yields.Such reactions are often conducted under reducing conditions with (TMSlsSiH, even though the reactions are not reductions and often finish with oxidative rearomatization. Reaction (68) shows an example where a solution containing silane (2 equiv) and AIBN (2 equiv) is slowly added (8h) in heated pyridine containing 2-bromopyridine (1 equiv) The synthesis of 2,3 -bipyridine 75 presumably occurs via the formation of cyclohexadienyl radicals 74 and its rearomatization by disproportionation with the alkyl radical from AIBN. ... 

The small Hammett p value of +0.16 observed for a series of related meta- and para-substituted mandelic acids indicates that there is a very small negative charge development on the benzyl carbon in the transition state of the rate-determining step of the pyridine catalysed oxidation of mandelic acid. The large positive AS value (+24 e.u./mol) found for the catalysed reaction led Banetjee and coworkers to conclude that the transition state (Figure 5) is product-like . This conclusion is consistent with the small f n/f D that is observed in this reaction164. The Pb—O bond is shown to rupture in a heterolytic fashion because Partch and Monthony185 have demonstrated that pyridine diverts the reaction from a homolytic to a heterolytic mechanism. 

Observation (iii) above, taken in the context of the triad annihilation in Scheme 12, indicates that the more or less statistical o/p pattern is diagnostic of the homolytic pathway (66) since it will clearly dominate the competition for TOL+- at the high concentrations of added N02 (Scheme 16). Indeed this conclusion is supported by observation (i), in which essentially the same isomeric product distribution (i.e. ortho meta para 70 2 28%) is achieved when the pyridine competition is thwarted for the sterically hindered 2,6-lutidine, an ineffective nucleophile (Schlesener et al., 1984). According to the formulation in Scheme 16, the isomeric product distribution is established from the sterically hindered Me2PyNOj during the homolytic annihilation of TOL+- by N02, most favourably at the ortho and para... 

Fig. 17 Variation of the rate constants for the homolytic (k2) and nucleophilic (k2) annihilation of various aromatic cation radicals with N02 and pyridine, respectively, as a function of the oxidation potential E x (to gauge ArH+ stability).

Since the latter conditions pertain to aromatic nitration solely via the homolytic annihilation of the cation radical in Scheme 16, it follows from the isomeric distributions in (81) that the electrophilic nitrations of the less reactive aromatic donors (toluene, mesitylene, anisole, etc.) also proceed via Scheme 19. If so, why do the electrophilic and charge-transfer pathways diverge when the less reactive aromatic donors are treated with other /V-nitropyridinium reagents, particularly those derived from the electron-rich MeOPy and MePy The conundrum is cleanly resolved in Fig. 17, which shows the rate of homolytic annihilation of aromatic cation radicals by NO, (k2) to be singularly insensitive to cation-radical stability, as evaluated by x. By contrast, the rate of nucleophilic annihilation of ArH+- by pyridine (k2) shows a distinctive downward trend decreasing monotonically from toluene cation radical to anthracene cation radical. Indeed, the... 

It is clear from a study of thermal and radical-induced decompositions of N-alkoxycarbonyldihydropyridines that radical processes are of minor importance, and that pyridine formation is probably a consequence of 1,2-elimination of formate (Scheme 6). It has also been concluded that the rate of 1,4-elimination of formate from iV-alkoxycarbonyl-l,4-dihydropyridines at higher temperatures is too rapid to be explained by a homolytic process. 

The fact that such selectivity was not found with homolytic alkylation of nonprotonated heteroaromatics (Table I) or with homocyclic aromatics indicates that polar factors play a major role in the reactivity of alkyl radicals with protonated bases. These effects were determined by the study of the relative reaction rates in the alkylation of 4-substituted pyridines in acidic medium. The results obtained with methyl, n-propyl, w-butyl, sec-butyl, i-butyl, and benzyl radicals are summarized in Table III. 

Relative Rates and Partial Rate Factors fob Homolytic Phenylation or Pyridine, Quinoline, and Benzothiazole... 

Methylation is taken as illustrative of alkylation for comparative purposes in Table 25 however, a wide range of other alkylations have been studied (76MI20503). Photolysis of di-r-butyl peroxide in a mixture of cyclohexane and pyridine gives cyclohexylation (equation 170) (7lCR(C)(272)854>. The relative rates for homolytic substitution of pyridines by cyclic alkyl radicals have been obtained (74JCS(P2)1699). A striking contrast can be seen (Table 26)... 

Phenylation of quinoline with benzoyl peroxide is easier (qpl,nR 5.0) than that of pyridine (71BSF2612). Substitution takes place at all carbons, and partial rate factors (F2 = 3.3, F3 = 1.8, F4 = 5.4, Fs = 6.6, F6 = 1.5, F7 = 1.6, F8 = 9.6) were obtained at 1% conversion. Homolytic arylation of quinoline is not of much synthetic value as reactions taken to higher conversion suffer not only from lack of selectivity, but di- and poly-substitution also take place. 

There are virtually no reports of homolytic reactions on the triazolo-pyridines. Unsuccessful attempts have been made to treat triazolopyridine (1) with methyl radicals,25 and a free radical mechanism is suggested as a possibility in the replacement of the methylthio group by chlorine (Section IV,C).208... 

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. 

Homolytic (free-radical) substitution may occur in any of the 2 to 6 positions of pyridine. Thus, the reaction of pyridine with benzene-diazonium salts gives a mixture of 2-, 3-, and 4-phenylpyridine. 

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