Electrophilic substitution in pyridine

Pyridine lies near one extreme in being far less reactive than benzene toward substitution by electrophilic reagents. In this respect it resembles strongly deactivated aromatic compounds such as nitrobenzene. It is incapable of being acylated or alkylated under Friedel-Crafts conditions, but can be sulfonated at high temperature. Electrophilic substitution in pyridine, when it does occur, takes place at C-3. 

Fig. 9.2. Plot of

Despite its V excessive character (340), thiazole, just as pyridine, is resistant to electrophilic substitution. In both cases the ring nitrogen deactivates the heterocyclic nucleus toward electrophilic attack. Moreover, most electrophilic substitutions, which are performed in acidic medium, involve the protonated form of thiazole or some quaternary thiazolium derivatives, whose reactivity toward electrophiles is still lower than that of the free base. 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

A kinetic study of the electrophilic substitution of pyridine-N-oxides has also been carried out50b,c. Rate-acidity dependencies were unfortunately given in graphical form only and the rate parameters (determined mostly over a 30 °C range) are given in Table 4b. There is considerable confusion in Tables 3 and 5 of the original paper, where the rate coefficients are labelled as referring to the free base. In fact the rate coefficients for the first three substituted compounds in... 

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. 

Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution. In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4 (the antithesis of the effect of resonance in pyridine itself). 

The preferred position for electrophilic substitution in the pyridine ring is the 3 position. Because of the sluggishness of the reactions of pyridine, these are often carried out at elevated temperatures, where a free radical mechanism may be operative. If these reactions are eliminated from consideration, substitution at the 3 position is found to be general for electrophilic reactions of coordinated pyridine, except for the nitration of pyridine-N-oxide (30, 51). The mercuration of pyridine with mercuric acetate proceeds via the coordination complex and gives the anticipated product with substitution in the 3 position (72). The bromina-tion of pyridine-N-oxide in fuming sulfuric acid goes via a complex with sulfur trioxide and gives 3-bromopyridine-N-oxide as the chief product (80). In this case the coordination presumably deactivates the pyridine nucleus in the 2 and... 

The intrinsic difficulty of electrophilic substitution of pyridines and azines is exacerbated because most of these reactions are carried out in acidic conditions where the pyridine nitrogen atom has become protonated. However, although electrophilic reagents react at the nitrogen atoms very readily, these reactions are often reversible, and even in strongly acidic solution there is a small proportion of the free base present. Thus, a priori, reaction is possible either on the conjugate acid majority species... 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

Electrophilic substitution occurs at the 3 and 5 positions, but usually requires drastic conditions because the species actually being attacked is a pyndinium ion. For example, nitration of pyridine with KNUj and concentrated H2SO4 at 300°C gives a 15% yield of 3-nilropyridine. Electrophilic substitution in the pyridine ring is facilitated by the presence of electron-donating substituents. 

We assume that readers are familiar with facts concerning the similarities and differences between benzene and pyridine derivatives. Pyridine is a base (pKa = 5.19, affording a pH of 8.5 for a 20% aqueous solution. It has a dipole moment of 2.15 D, as seen in Table 3). The fact that the nitrogen heteroatom with a higher electronegativity than carbon causes a depletion of 7i-electrons in y and in a positions leads to regioselective electrophilic substitution in p positions and, conversely, facilitates nucleophilic attack mainly in a positions, e.g., affording a-picoline and lithium hydride from the reaction of pyridine with methyllithium. 

Although the 1,3,4-thiadiazole ring is classed as Ti-excessive according to Albert, the presence of two nitrogen atoms of pyridine type in the ring leaves the carbon atoms with rather low electron density, and consequently no electrophilic substitutions in the unsubstituted... 

Regioselective nucleophilic, electrophilic, and radical substitution in pyridines, di-, tri-, and tetrazines 88AHC(44)199. 

Pyridine is frequently oxidized to pyridine oxide (equation 503) [729, 210, 263], Pyridine oxide is an oxidant capable of hydroxylating aromatic rings [994. But more important, the presence of oxygen on the nitrogen of the pyridine ring reverses the direction of electrophilic substitutions in the pyridine ring. Whereas electrophilic attacks on pyridine occur in P positions, attacks on pyridine oxide occur in a and -y positions. After the introduction of the electrophiles, the pyridine oxide is converted into pyridine by mild reductions, such as treatment with salts of iron or titanium. 

Here, as in electrophilic substitution, the pyridine ring resembles a benzene ring that contains strongly electron-withdrawing groups. Nucleophilic substitution takes place readily, particularly at the 2- and 4-positions. For example ... 

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

---