Picoline with phenyllithium

The orientation in the reaction of organolithium compounds with 3-substituted pyridines had not always been unambiguously established. For example, it was reported that 3-picoline and phenyllithium combined to give 5-methyl-2-phenylpyridine (107, R = CH3) exclusively.240 This has been shown to be quite the opposite of what actually happens241 (see Table IV). Similarly, 3-phenylpyridine was said to... 

There is no doubt that in these. reactions the nitrogen atom of the pyridine ring is complexed with either the lithium alkyl or aryl or with the lithium bromide which is usually present in many preparations of organolithium compounds. It has been established that, either in the presence of an excess of lithium bromide or in the total absence of this salt, phenyllithium still gives the same ortho .para ratio on reaction with 3-picoline.229 To account for the predominant formation of the 2,3-isomer in the reaction of CH3Li with 3-alkylpyridines, it was suggested261 that the transition states for these reactions were similar... 

In all the above cases, C-2 is activated toward attack by phenyllithium compared with the same position in pyridine, while C-6 is about six- to sevenfold deactivated by the 3-methyl or 3-ethyl group compared with the oc-position of pyridine. Also, the 2,3- 2,5-isomer ratios remained unchanged in all cases. A 3-methyl group activates C-2 more than does a 3-ethyl, the activation in the former case being sufficient to overcome the deactivation of C-6 and resulting in an over-all activation of the 3-picoline nucleus compared with that of pyridine and a value of the total rate ratio greater than unity. In the case of 3-ethylpyridine, the activation is insufficient to overcome the normal deactivation of the position para to the alkyl group. 

Molecular orbital calculations of the w-electron distribution in pyridine predict that more 4- than 2-aminopyridine should be formed in the Tschitschibabin reaction.4 The fact that no 4-aminopyridine can be detected when the two positions are allowed to compete for a deficiency of sodamide (see, e.g., Abramovitch et al 268) has led to the suggestion that the observed orientation in this reaction depends on the relative ease of elimination of a hydride ion from C-2 and C-4 and not upon the initial mode of addition (which, by implication, must take place predominantly at C-4 as predicted by the molecular orbital calculations).4 This hypothesis necessitates that the addition step be rapidly reversible and that the second stage, the elimination of hydride ion, be the rate-determining one (Scheme VII). Although it seems reasonable to assume that the hydride ion eliminations are the slow steps in this reaction, the fact that no deuterium isotope effect was observed in the reaction of 3-picoline-2d and of pyridine-2d with sodamide implies that the first stage must be virtually irreversible,268 as was found also in the case of the addition of phenyllithium to pyridine.229 The addition stage must, therefore, be the product-... 

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