Electrophilic substitution Of pyridine

Pyridine, like benzene, has six Jl-electrons. The electron-withdrawing nitrogen atom deactivates the ring, and electrophilic substitution is slower than that for benzene. Substitution occurs principally at the 3-position of the ring, as attack at the 2-/4-position produces less stable cation intermediates (i.e. with one resonance structure having a positive charge on the divalent nitrogen). 

Nitrogen lone pair is not part of the aromatic sextet 

4-Methylbenzoic acid is otherwise known as p-toluic acid 

As naphthalene (CioHg) is aromatic (10 7C electrons), it also undergoes electrophilic substitution reactions. Attack occurs selectively at the C-1 position, rather than the C-2 position, because the intermediate carbocation is more stable (i.e. two resonance stmctures can be drawn with an intact benzene ring for attack at C-2, only one can be drawn with an intact benzene ring). 

For sulfonation (using H2SO4), the position of attack depends on the reaction temperature. At 80 °C, attack at C-1 occurs (as expected), and the 1-sulfonic acid is formed under kinetic control (Section 4.9.3). However, at higher temperatures (e.g. 160 °C), attack at C-2 predominates and the 2-sulfonic acid is formed under thermodynamic control. The C-1 isomer is thermodynamically less stable than the C-2 isomer because of an unfavourable steric interaction with the hydrogen atom at C-8 (this is called a peri interaction). 

Pyridine is commonly used as a base in (nganic synthesis (Seetion 1.7.5). The lone pair of eleetrons on nitrogen is not part of the aromatic ring 

---

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... 

This short summary has aimed to highlight a few of the more important aspects of the orientation of electrophilic substitution of pyridines and their benzo analogues. Strictly, reactions that involve metallation could be treated under this heading but they will be considered as involving a nucleophilic attack at a ring hydrogen (see Section 2.05.5). Electrophilic cyclizations of a substituent on to a pyridine will be mentioned briefly, but Chapter 2.06 should be consulted for those reactions. 

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... 

Electrophilic substitution of pyridine is further hindered by the tendency of the nitrogen atom to attack electrophiles and take on a positive charge. The positively charged pyridinium ion is even more resistant than pyridine to electrophilic substitution. 

Two electrophilic substitutions of pyridine are shown here. Notice that these reactions require severe conditions, and the yields are poor to fair. 

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... 

Activating substimtents," i.e. groups that can release electrons either inductively or especially meso-merically, make the electrophilic substitution of pyridine rings to which they are attached faster for example... 

In most cases, electrophilic substitution of pyridines occurs very much less readily than for the correspondingly substituted benzene. The main reason is that the electrophilic reagent, or a proton in the reaction medium, adds first to the pyridine nitrogen, generating a pyridinium cation, which is naturally very resistant to attack by an electrophile. When it does occur, electrophilic substitution at carbon must involve either highly unfavoured attack on a pyridinium cation or a relatively easier attack, but on a very low equilibrium concentration of uncharged free pyridine base. 

Electrophilic substitution of pyridine, pyrimidine, quinoline, and the like is difficult to effect, whereas nucleophilic introduction of NH2 or OH at the oc-and the y-position to nitrogen, and ring-closure syntheses of iV-heterocycles containing NH2 or OH substituents, are relatively easy. Therefore, in laboratory work, those methods are when possible used in which a NH2 or an OH group is replaced by halogen examples are the preparation of 2- and 4-bromo-pyridine (see pages 264 and 241) and 2-chloropyrimidine (see pages 259 and 241). 

Electrophilic substitution of pyridine by halogen occurs at the 3- and the 5-position thus bromination of pyridinium chloride in the presence of HgCl2 (10 g per 100 g of pyridine) in a metal bath at 212-215° gives 3-bromo- or 3,5-dibromopyridine as main product according to the amount of bromine used.734,735 Raising the temperature at which pyridine is halogenated reverses the type of substitution, as in the bromination of halobenzenes. 

Activating substitutents, i.e. groups which can release electrons either inductively or mesomerically, make the electrophilic substitution of pyridine rings to which they are attached faster, for example 4-pyridone nitrates at the 3-position via the O-protonated salt. In order to understand the activation, it is helpful to view the species attacked as a (protonated) phenol-like substrate. Electrophilic attack on neutral pyridones is best visualised as attack on an enamide. Dimethoxypyridines also undergo nitration via their cations, but the balance is often delicate, for example 2-aminopyridine brominates at C-5, in acidic solution, via the free base. ... 

An ab initio smdy suggests that the formation of a Diels-Alder adduct [i.e. (23)] from reaction between 1-methylpyrrole and dimethyl acetylenedicarboxylate is favoured over the formation of a possible Michael-type addition product (24). Both pathways involve an initial electrophilic substitution at the 2-position of the pyrrole to form a zwitterionic intermediate. A review, in Chinese, concerns a number of electrophilic substitutions of pyridine. A kinetic study has been made of the reaction between 4,6-dinitrobenzofuroxan (25) and various anilines in acidic H2O-DMSO... 

The implications of the data of Table 5.37 for orientation and for activation should be considered separately. For electrophilic substitution in both pyridine and pyridinium (the situation in which is represented by giving An a high value), C(3) is always indicated to be the most reactive position. The relative order of C(2) and C(4> (for which there is no direct evidence) depends upon the assumptions made, in particular as to whether the auxiliary inductive effect operates at C(2) when that is the position of localization. For pyridine 1-oxide C(2) is always the most reactive position, and with the preferred parameters, the complete sequence is C(2) > C(4) > C(3). In contrast, for the protonated oxide, C(3) is the favoured position, and these results led Barnes 20 correctly to conclude that in electrophilic substitutions of pyridine 1-oxide which proceeded at C(4) the free base was involved, as against the conjugate acid in those which proceeded at C(3). In the former case, C(4) rather than C(2) was attacked because of a steric factor. 

---