Pyridine, aromaticity electrophilic substitution reactions

There is another important factor in the low reactivity of pyridine derivatives toward electrophilic substitution. The —N=CH— unit is basic because the electron pair on nitrogen is not part of the aromatic n system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

Electrophilic substitutions Pyridine s electron-withdrawing nitrogen causes the ring carbons to have significantly less electron density than the ring carbons of benzene. Thus, pyridine is less reactive than benzene towards electrophilic aromatic substitution. However, pyridine undergoes some electrophilic substitution reactions under drastic conditions, e.g. high temperature, and the yields of these reactions are usually quite low. The main substitution takes place at C-3. 

Aromatic electrophilic substitution on pyridine is not a useful reaction. The ring is unreactive and the electrophilic reagents attack nitrogen making the ring even less reactive. Avoid nitration, sulfonation, halogenation, and Friedel-Crafts reactions on simple pyridines. 

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 ... 

To summarize, the reactivity of oxazoles closely resembles that of the ftirans, especially in their readiness to undergo ring-opening reactions and [4+2] cycloadditions. The pyridine-like N-atom impedes electrophilic substitution reactions. On the other hand, it facilitates the attack of nucleophiles onto the C-2 atom. Although oxazole is considered to be a heteroarene, because of its six delocalized ring electrons, its aromaticity is low and comparable to that of furan. 

Unlike benzene, pyridine undergoes electrophilic aromatic substitution reactions with great difficulty. Halogenation can be carried out under drastic conditions, but nitration occurs in very low yield, and Friedel-Crafts reactions are not successful. Reactions usually give the 3-substituted product. 

Problem 24.22 Electrophilic aromatic substitution reactions of pyridine normally occur at C3. Draw... 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

Electrophilic substitution in benzo[fe]thieno- and benzo[fe]furo-[2,3-c]pyridines (2) occurs mainly at the 6-position, although when this position is blocked by Cl in a related structure 5-,7-, and 8-substituted products are formed. The usefulness of triflu-oromethanesulfonic acid as a new solvent with CFCI3 for the reaction of fluorine with aromatics has been explored. Fluorobenzene gives 1,4-difluorobenzene (31%) and 1,2-difluorobenzene (7%) instead of the addition products mainly observed when the acid is absent 1,2- and 1,3- but not 1,4-difluorobenzene undergo further substitution at appropriate acidity. 

Electrophilic aromatic substitutions Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitution generally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

Predict the product of electrophilic aromatic substitution reactions of pyridine and quinoline. 

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