Pyridine delocalisation

Pyridine (62), like benzene, has six n electrons (one being supplied by nitrogen) in delocalised n orbitals but, unlike benzene, the orbitals will be deformed by being attracted towards the nitrogen atom because of the latter s being more electronegative than carbon. This is reflected in the dipole of pyridine, which has the negative end on N and the positive end on the nucleus ... 

Pyrrole (68) also has 6n electrons in delocalised n orbitals, but here the nitrogen atom has to contribute two electrons to make up the six (thus becoming essentially non-basic in the process, cf. p. 73), and the dipole of pyrrole is found to be in the opposite direction to that of pyridine, i.e. with the positive end on nitrogen and the negative end on the nucleus ... 

Electrochemical reduction of 1-alkylpyridinium salts 1 leads to Are addition of one electron with the formation of a ii-delocalised radical-zwitterion. This is a formally neutral species. Botlr this species and the N-protonated pyridine radical-anion are essentially n-delocalised radicals. The radical-zwitterion from 1-methylpyridinium shows a long wavelength absorption band in water with 7, ax 750 nm [19]. The nitrogen ring radical-zwitterions take up further electrons at more... 

Figure 8-16. A valence bond representation of a co-ordinated pyridine. The positive charge is delocalised and the 2- and the 4-positions of the ligand develop electrophilic character.

Thus, delocalisation of the nitrogen lone pair completes the sextet of electrons required for aromaticity. These two examples illustrate the point that certain heterocycles (closely analogous to benzene and naphthalene) such as pyridine 5.1, pyrimidine 10.1, and quinoline 6.1 are aromatic by right whereas other heterocycles such as pyrrole 2.1, imidazole 3.2, and triazole 8.7 have to earn aromaticity by delocalisation of a lone pair of electrons from the heteroatom. 

The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2-azoles are significantly less basic than the 1,3-azoles because of the electron-withdrawing effect of the adjacent heteroatom. Isoxazole and isothiazole are essentially non-basic heterocycles (pAas <0), and even pyrazole (pAa=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pAa=7). 

Pyridine can be attacked by nucleophiles at the C2/C6 and C4 positions in a manner analogous to the addition of nucleophiles to a carbonyl group in a 1,2 or 1,4 fashion. Attack at the C3/C5 positions is not favoured because the negative charge on the intermediate cannot be delocalised onto the electronegative nitrogen atom. 

Just as a carbonyl group stabilises an adjacent negative charge as an enolate anion, so the anion derived from 2-methyl pyridine is stabilised by delocalisation of the negative charge onto the electronegative nitrogen atom. 

Alkyl groups at the C2 and C4 positions of quinoline can be deprotonated by strong bases. This is because (as with pyridine) the negative charge on the resultant carbanions can be delocalised onto the electronegative nitrogen atom, as in carbanion 6.27a,b. 

The pKa of 3-methylpyridine, whose anion cannot be delocalised onto N, is closer to that of toluene, and deprotonation gives only low yields with most bases. However, with a combination of BuLi and lithio-dimethylaminoethanol (LiDMAE) deprotonation is quantitative but yields products 471 arising from apparent lithiation a to N 426 Trying to force lateral lithiation of pyridines is generally doomed to failure, as ring lithiation or nucleophilic addition usually takes place first.365... 

Birch reduction of aromatic heterocycles is equally rewarding if more challenging mechanistically. The pyridine diester 138 is reduced to an intermediate that could be drawn as 139. Both anions are extended enolates but one has the charge delocalised onto the nitrogen atom and so is less reactive than the other. Alkylation occurs at the a-position38 to give 140. 

Pyridine has all the disadvantages of benzene plus some special ones of its own. Attack at the 2- or 4-positions 4 gives intermediate cations such as 5 which have part of the positive charge delocalised onto nitrogen 5c. This would be no bad thing if the nitrogen atom were tetravalent like stable NH4+, but it is actually divalent like the unknown, electron-deficient, and presumably very unstable NH2+. 

Attack at the 3-position 6 is not so bad as the intermediate cation 7 is no longer delocalised onto the electron-deficient nitrogen atom but is not as stable as the benzene intermediate 5 and the slow step is very slow because the HOMO of pyridine is lower in energy than the HOMO of benzene. 

Nitration of 28 X = OMe is successful because both electron-donating OMe and NH2 groups activate the 3-position and the intermediate cation 31 is delocalised over both N and O atoms. We could have used lone pairs on either the OMe or NH2 groups to draw the mechanism 30. The reaction occurs in spite of the pyridine ring rather than because of it. The position of attack - C3 or C5 - is not easily predicted and searching the literature or trial and error is needed. 

Every additional nitrogen atom must be of the pyridine sort and this has the curious effect of increasing both the acidity and the basicity. There is another difference. Protonation now occurs on the pyridine-like nitrogen atom but both nitrogen atoms cooperate to deliver electrons in both pyrazole 111 and imidazole 112. In this process the pyridine-like nitrogen atom becomes pyrrole-like and vice versa but this is merely formal as the cations 110 and 113 are symmetrically delocalised and the two nitrogen atoms are equivalent. 

The special properties associated with pyridine a- and y-positions are evident again in the reactions of alkyl-pyridines protons on alkyl groups at those positions are particularly acidified because the enaminate anions formed by side-chain deprotonation are delocalised. The ability to form side-chain anions provides a useful means for the manipulation of a- and y-side-chains. 

A significant difference in this typical behaviour applies to the isoquinoline 3-position - the special reactivity that the discussion above has developed for positions a to pyridine nitrogen, and that also applies to the isoquinofine 1-position, does not apply at C-3. In the context of nucleophilic displacements, for example, an intermediate for reaction of a 3-halo-isoquinoline cannot achieve delocalisation of negative charge onto the nitrogen unless the aromaticity of the benzene ring is disrupted. Therefore, such intermediates are considerably less stabilised and reactivity considerably tempered. 

The three amino-pyridines are all more basic than pyridine itself and form crystalline salts by protonation at the ring nitrogen. The a- and y-isomers are monobasic only, because charge delocalisation over both nitrogen atoms, in the manner of an amidinium cation, prevents the addition of a second proton. The effect of the delocalisation is strongest in 4-aminopyridine 9.1) and much weaker in 2-aminopyridine (p/ aH 7.2). Delocalisation is not possible for the P-isomer, which thus can form a di-cation in strong acid (p/faHS 6.6 and -1.5). " ... 

Diazine alkyl groups, with the exception of those at the 5-position of pyrimidine, can undergo condensation reactions that utilise a side-chain carbanion produced by removal of a proton. As in pyridine chemistry, formation of these anions is made possible by delocalisation of the charge onto one (or more) of the ring nitrogen atoms. 

Pyridines form crystalline, frequently hygroscopic, salts with most protic acids. Pyridine itself, with pATa 5.2 in water, is a much weaker base than saturated aliphatic amines which have pATa values mostly between 9 and 11. Since the gas-phase proton affinity of pyridine is actually very similar to those of aliphatic amines, the observed solution values reflect relatively strong solvation of aliphatic ammonium cations this difference may in turn be related to the mesomerically delocalised charge in pyridinium ions and the consequent reduced requirement for external stabilisation via solvation. 

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