Pyridine direct electrophilic substitution

For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in cone, sulfuric acid) at 130 °C (Scheme 2.4). Direct electrophilic substitution is not involved, however, aszwitterionic (dipolar) pyridinium-A-sulfonate is the substrate for an addition of bromide ion. Subsequently, the dihydropyridine that is formed reacts, possibly as a dienamine, with bromine to generate a dibromide, which then eliminates bromide ion from C-2. It is notable that no bromination occurs under similar conditions when oleum is replaced by cone, sulfuric acid alone instead, pyridinium hydrogensul-fate is produced. 

Part III - Surprisingly Successful Direct Electrophilic Substitutions Sulfonation and halogenation at the 3-position in strong sulfuric acid The reaction with SOCl2 reaction at the 4-position, synthesis ofDMAP Part IV - Successful Nitration of Pyridine... 

A limited use of direct electrophilic substitution combined with halogen/lithium exchange or orf/to-lithiation allows us to make a variety of pyridines and quinolines. When the N-oxides are used as well, the scope is even wider. Nucleophilic substitution extends this still further. In the next chapter (33) we shall see that electrophilic oxygen can also be added to pyridines. What is missing is the direct formation of 3-substituted pyridines this is dealt with in the next section. 

When, as in the omeprazole and caerulomycin syntheses, an N-oxide has a number of functions, it is worth building in this extra functionality. Only 4-substituted pyridines can be made from the iV-oxidc the 3-isomers must be made available by direct electrophilic substitution on pyridines themselves and fortunately some direct methods do work, though it is not immediately clear why they do Direct sulfonation19 and bromination20 both work well in very strong sulfuric acid, giving the 3-sulfonic acid 152 and 3-bromopyridine 153 in good yield. 

Also surprising is the conversion of nicotinic acid chloride hydrochloride into 5-bromonicotinic acid in 87 per cent yield, by heating with bromine at 150-170°. Direct chlorination was much less successfuP . This may be a direct electrophilic substitution, but the nicotinic acid chloride hydrochloride was prepared from nicotinic acid and thionyl chloride (see p. 322), and it is just possible that the reaction is related to the substitutions into pyridine-thionyl chloride complexes discussed below (p. 228). It might even be that nicotinic acid chloride hydrochloride is not a simple salt but possesses a structure like the pyridine-thionyl chloride complex. 

The next stage of the synthesis was concerned with introduction of the missing amino substituent into the vacant position in the pyridine ring of (103). Since direct electrophilic substitution of this pyridine ring in the presence of the highly oxygenated D-ring did not appear feasible (cf. 55, 58), a more circuitous route was necessary. Thus, pyridine (103) was... 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

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). 

Electrophilic chlorination of quinoline under neutral conditions occurs in the orientation order 3 > 6 > 8. Hammett ct+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. The reactivity order can be affected by substitution of an electron-withdrawing group in the benzene ring, which directs the chlorination to the pyridine ring. Thus, NCS in acetic acid or sulfuryl chloride in o-dichlorobenzene converts 8-nitroquinoline into 3-chloro-8-nitroquinoline in high yield (91M935). 

The SHMO orbitals of pyrrole, pyridine, and pyridinium are shown in Figure 11.6. The HOMO of pyrrole is the same as that of butadiene. Thus pyrrole is more reactive than benzene toward electrophilic attack. Attack, leading to substitution, occurs mainly at the 2- and 5-positions where the electron density of the HOMO is concentrated. In the case of pyridine (Figure 11.6b), the HOMO is not the n orbital, but the nonbonded MO, wn, which would be situated at approximately a - 0.5 //. Thus, it is not pyridine but pyridinium (Figure 11.6c) which undergoes electrophilic attack and substitution. The reactivity is much less than that of benzene, although this could not be deduced directly from the SHMO calculation. Neither does the calculation suggest the reason that electrophilic substitution occurs mainly at the 3- and 5-positions, since the n HOMO is... 

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. 

Pyridine itself can be converted into 3-nitropyridine only inefficiently by direct nitration, even with extremely vigorons conditions, however a couple of ring methyl groups facihtate electrophilic substitution snfficiently to allow nitration both collidine (2,4,6-trimethylpyridine) and its M-methyl quaternary salt are nitrated at similar rates under the same conditions, showing that the former reacts via its A -protonic salt. Steric or/and inductive inhibition of M-nitration allows C-3-substitution using nitronium tetrafluo-roborate an example is the nitration of 2,6-dichloropyridine or of 2,6-difluoropyridine using tetramethyl-ammoninm nitrate with trifluoromethansulfonic anhydride. ... 

Electrophilic substitution is difficult with electron-deficient heteroatomic compounds such as pyridine and quinoline. However, an electrophile can be readily introduced when the heterocycles have an effective ortho-directing group such as a sulfamoyl moiety. Lithiation of the 2-pyridinesulfonamide (51) was performed at low temperature by using 2 equivalents of LDA in ether at —78 °C for 1.5 h (equation 27). Addition of benzophenone to the solution of 52 gave the adduct in high yield38. Metallation of the 4-pyr-idinesulfonamide 53 with 3 equivalents of LDA, followed by reaction with benzaldehyde, afforded the 3,5-disubstituted pyridine 54 (equation 28). 

The carbons of a pyridine are, in any case, electron-poor, particularly at the a-and 7-positions formation of a cr-complex between a pyridine and an electrophile is intrinsically disfavoured. The least disfavoured, i.e. best option, is attack at a j3-position - resonance contributors to the cation thus produced, do not include one with the particularly unfavourable sextet, positively-charged nitrogen situation (shown in parentheses for the a- and 7-intermediates). The situation has a direct counterpart in benzene chemistry where a consideration of possible intermediates for electrophilic substitution of nitrobenzene provides a rationalisation of the observed meta selectivity. 

Pyridine itself can be converted into 3-nitropyridine only inefficiently by direct nitration even with vigorous conditions, as shown below, however a couple of ring methyl groups facilitate electrophilic substitution sufficiently to allow nitration to... 

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