Electrophilic substitution pyridine susceptibility

Although resistant to electrophilic substitution, pyridine undergoes nucleophilic aromatic substitution. The pyridine ring is partially positive (due to electron withdrawal by the nitrogen) and is therefore susceptible to attack by nucleophiles. Here are two examples ... 

The consequences of this replacement gives pyridine a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to... 

Furthermore, the strongly metallic character of selenium weakens the C-Se bond and thus favors reactions involving opening of the ring. The basicity of the three heterocycles is approximately in the same order, the nitrogen atom of selenazole and thiazole possessing much the same properties as the heteroatom of pyridine. Of the two carbon atoms ortho to nitrogen, that is, the 2-carbon and the 4-carbon, only the one in the 2-position is fairly active as a result of its interaction with selenium or sulfur. The 4- and 5-positions of thiazole and selenazole are more susceptible to electrophilic substitution than the 3- and 5-positions of pyridine. This is particularly true of the 5-position of selenazole. Thus it can be said that the 2- and 5-positions of the selenazoles and thiazoles... 

The weaker the basicity of the pyridine nitrogen, the more likely it is that the reaction could occur on the free base. a-Halogen atoms are particularly effective, in that they sharply reduce basicity but not very much the susceptibility toward electrophilic substitution. 

Pyridine is virtually inert to aromatic electrophilic substitution. Consider nitration of pyridine by nitric acid. First, as pyridine is a moderate base, it will be almost completely protonated by the acid, making it much less susceptible to electrophilic attack. Second, addition of the electrophile to the small amount of unprotonated pyridine present in solution is not a facile process. 

Attempts to correlate reaction mechanisms, electron density calculations and experimental results have met with only limited success. As mentioned in the previous chapter (Section 4.06.2), the predicted orders of electrophilic substitution for imidazole (C-5 > -2 > -4) and benzimidazole (C-7>-6>-5>-4 -2) do not take into account the tautomeric equivalence of the 4- and 5-positions of imidazole and the 4- and 7-, 5- and 6-positions of benzimidazole. When this is taken into account the predictions are in accord with the observed orientations of attack in imidazole. Much the same predictions can be made by considering the imidazole molecule to be a combination of pyrrole and pyridine (74) — the most likely site for electrophilic attack is C-5. Furthermore, while sets of resonance structures for the imidazole and benzimidazole neutral molecules (Schemes 1 and 2, Section 4.06.2) suggest that all ring carbons have some susceptibility to electrophilic attack, consideration of the stabilities of the expected tr-intermediates (Scheme 29) supports the commonly observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first at C-5 and a second substituent enters at C-6 unless other substituent effects intervene. 

The consequence of this replacement gives pyridine a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. An avenue of chemistry not possible with benzene is the formation of pyridinium salts by donation of the nitrogen lone pair electrons. The resultant salts are still aromatic, however they are much more polarized. This is reflected by the apparent acidity of the corresponding conjugate acid (pK, 5.2) compared to the acidity of the corresponding conjugate acid of piperidine (pK, 11.1). 

The chemical reactivity of simple heterocyclic aromatic compounds varies widely in electrophilic substitution reactions, thiophene is similar to benzene and pyridine is less reactive than benzene, while furan and pyrrole are susceptible to polymerization reactions conversely, pyridine is more readily susceptible than benzene to attack by nucleophilic reagents. These differences are to a considerable extent reflected in the susceptibility of these compounds and their benzo analogues to microbial degradation. In contrast to the almost universal dioxygenation reaction used for the bacterial degradation of aromatic hydrocarbons, two broad mechanisms operate for heterocyclic aromatic compounds ... 

The formal replacement of a CH in benzene by N leads to far-reaching changes in typical reactivity pyridines are much less susceptible to electrophilic substitution than benzene and much more susceptible to nucleophilic attack. However, pyridine undergoes a range of simple electrophilic additions, some reversible, some forming isolable products, each involving donation of the nitrogen lone pair to an electrophile, and thence the formation of pyridinium salts which, of course, do not have a counterpart in benzene chemistry at all. The ready donation of the pyridine lone pair in this way does not destroy the aromatic... 

A striking difference between pyridines and their A-oxides is the susceptibility of the latter to electrophilic nitration. This can be understood in terms of mesomeric release from the oxide oxygen, and is parallel to electron release by oxygen and hence increased reactivity towards electrophilic substitution in phenols and phenoxides. One can find support for this rationalisation by a comparison of the dipole moments of trimethylamine and its A-oxide, on the one hand, and pyridine and its A-oxide, on the other the difference... 

In addition to the propensity for electrophilic substitution at C-l/C-3 (see above), the main feature of this class of heterocycle is that they undergo relatively easy nucleophilic attack in the six-membered ring, which is now distinctly electron-deficient through the incorporation of imine units - the analogy with the ease of nucleophilic addition to diazines versus pyridines, is obvious. Some are so susceptible to nucleophilic addition that they form hydrates even on exposure to moist air. Preparative Uthiations can, however, be carried out using less nncleophilic bases. 

Practically all the reactions of quinolizinium ions are similar to those of pyridinium salts, thus they are resistant to electrophilic attack, but readily undergo nucleophilic addition, the initial adducts undergoing spontaneous electrocyclic ring opening to afford, finally, 2-substituted pyridines however the susceptibility of the cations to nucleophiles is not extreme - Uke simpler pyridinium salts they are stable to boiling water. 

Pyridine Woxide chemistry, which clearly has no parallel in benzenoid chemistry, is an extremely important and useful aspect of the chemistry of heterocycles of the pyridine series. The structure of these derivatives means that they are both more susceptible to electrophilic substitution and react more easily with nucleophiles - an extraordinary concept when first encountered. On the one hand, the formally negatively charged oxygen can release electrons to stabilise an intermediate from electrophilic attack and, on the other, the positively charged ring nitrogen can act as an electron sink to encourage nucleophilic addition. 

In contrast to pyridines that are very resistant to electrophilic substitution at carbon without strong activating substituents, quinolines and isoquinolines are susceptible for substitution on the benzene ring. Following the dipole density described above, positions C5 and C8 are the only positions prone to... 

Substituents which reduce the basicity of a pyridine nitrogen can also influence the susceptibility of the heterocycle to electrophilic substitution, in these cases by increasing the quantity of neutral (more reactive) pyridine present at equilibrium 2,6-dichloropyridine nitrates at C-3, as the free base, and only 10 times as slowly as 1,3-dichlorobenzene. As a rule-of-thumb it has been suggest-... 

Pyrazine and quinoxaline fV-oxides generally undergo similar reactions to their monoazine counterparts. In the case of pyridine fV-oxide the ring is activated both towards electrophilic and nucleophilic substitution reactions however, pyrazine fV-oxides are generally less susceptible to electrophilic attack and little work has been reported in this area. Nucleophilic activation generally appears to be more useful and a variety of nucleophilic substitution reactions have been exploited in the pyrazine, quinoxaline and phenazine series. 

Draw and compare Lewis structures for benzene and pyridine. How many 7C electrons does each molecule have Where are the most accessible electrons in each Display the electrostatic potential map for pyridine and compare it to the corresponding map for benzene. Would you expect electrophilic attack on pyridine to occur analogously to that in benzene If so, should pyridine be more or less susceptible to aromatic substitution than benzene If not, where would you expect electrophilic attack to occur Explain. 

The effect of the heteroatom is to make the pyridine ring very unreactive to normal electrophilic aromatic substitution. Conversely, pyridines are susceptible to nucleophilic attack. These topics are discussed later. 

---