Reactivity of the Pyridine Ring

On the other hand, pyridine is a weak base (p/Ta = 5.22) that can be protonated or can form salts with strong protonic acids. Some of the resulting pyridinium salts are commercial reagents. For instance, pyridinium perbromide is used as brominating agent, and pyridinium dichloromate 

Short-lived carbenes can react with pyridine to form the corresponding pyridinium ylide, which are far more stable than the starting carbenes. For example, pyridinium tungstate 33, prepared from phenyl ethoxy carbene 31 and dihydropyridine 32, serves as an effective cyclopropanation reagent to give products 34 and 35 in a 95 5 ratio and in 35% yield.  

In addition to reactions with amines, Zincke salts also react with other nitrogen nucleophiles, such as hydroxylamine and hydrazine, providing various A -substituted pyridine derivatives, such as pyridine N-oxides 39 and 7V-aminopyridinium salts 40. 

Reactions with A/-acyl or AAsulfonyl hydrazines gave rise to iminopyridinium ylides and ylide precursors such as 43 and 44. Benzwl hydrazines are also used in the Zincke reaction under simitar conditions.  

Zincke salts played an important role in the synthesis of NAD /NADH co-enzyme analogues. The nicotinamide-derived Zincke salt 41 has been widely used. For instance, Zincke salt 41 was used to link with various adenine derivatives via the tether having a phosphonate functionality (45- 46) to study through-space interaction between the pyridinium and base portions. 

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Methyl substituents on the pyridine ring had a profound impact on the reactivity of the pyridine ring. 2,6-Lutidine did not react to any appreciable extent on Ni(100) [12]. The infrared spectrum of 2,6-lutidine showed no C=C stretches and ring vibrations, but did show CH... 

A second factor that decreases the reactivity of the pyridine ring toward electrophilic attack is that acid-base complexation between the basic ring nitrogen atom and the attacking electrophile places a positive charge on the ring, further deactivating it. 

In general, the reactivity of the pyridine ring in nucleophilic substitution reaction decreases in the row C2 > C4 > C3. Consequently, more synthetic routes are reported for 4-fluoropyridines compared to 3-fluoropyridines. Pyridines can form cationic complexes with electrophiles resulting in activation of heterocyclic ring toward nucleophilic substitution. On the other hand, pyridines have signih-cantly reduced reactivity toward electrophiles and typically undergo electrophilic substitution reactions in the present of strong Lewis acids selectively in the position 3. ... 

Quinoline and isoquinoline, the two possible structures in which a benzene ring is annelated to a pyridine ring, represent an opportunity to examine the effect of fusing one aromatic ring to another. Clearly, both the effect the benzene ring has on the reactivity of the pyridine ring, and vice versa, and comparisons with the chemistry of naphthalene must be made. Thus the regiose-lectivity of electrophilic substitution, which in naphthalene is faster at an a-position, is mirrored in quinoline/isoquinoline chemistry by substitution at 5-... 

The 5-position is the preferred site for sulfonation (58. 392). This position is more reactive than any of the pyridine ring in. V-[pyridyl-(2)]-thiazolyl-(2)-amine (178) (132, 382, 383). 

Dipolar addition of mesitylene nitrile oxide with 4,7-phenanthroline 159 gave a 2 1 adduct 160 with a very low yield (Equation 19), the dearomatization of the pyridine ring giving rise to a more reactive double bond which, in turn, underwent cyclization <1998T9187>. 

The ring closure of 3-pyridylaminomethylenemalonates may lead to 1,5-naphthyridine or 1,7-naphthyridine, depending on which position of the pyridine ring (position 2 or 4) is involved in the cyclization (Scheme 45). Due to the higher reactivity of position 2 of 3-aminopyridine derivatives... 

He have found that, In hydrocarbon solvents, the activating effect of the pyridine ring upon the reactivity of the doublebond, allows nucleophilic addition from non-solvated R Mg R derivatives. 

In the coupling of 3-(2 -chloropyridyl)-triflate and ethyl acrylate (7.46.) steric and electronic factors both drive the pyridine moiety into the /3-position of the olefin.65 Although the 2-position of the pyridine ring is more activated, the enhanced reactivity of the triflate in oxidative addition leads to selective reaction in the 3-position. Analogous to some previously mentioned reactions involving triflates the addition of lithium chloride was found to accelerate the coupling (c.f 7.28.),... 

The inherent difference in the reactivity of the 2-, and 3-positions of the pyridine ring was also exploited in an industrial application of the carbonylative coupling of pyridines. 2,5-Dibromo-3-methylpyridine was converted into the 2-monoamides using different amines with a 98 2 selectivity. Keys to the success of the coupling, which was run on the 100 kg scale, were the use of DBU as base and the replacement of the phosphine in the catalyst with 2,2 -bipyridine.84 The carbonylation of 3,5-... 

Imidazo[4,5-b pyridines. Methyl chloride reacts with 78 at the nitrogen atom of the pyridine ring, but with 79 at the unsubstituted imidazole nitrogen atom.183 The Former result is surprising because it does not fit a prediction based on a consideration of the relative reactivities of pyridine and 1-methylimidazole.44... 

The pyrido[l,2-a]pyrimidines (256) undergo an essentially similar ring transformation, with the difference being that the ring closure of the intermediate iminoketene (257) takes place not to the C-3 atom of the pyridine ring but to the more reactive phenyl ring, and thus a quinoline derivative (258) is isolated.327... 

Heteroaromatic amines can oxidize to the corresponding N-oxide, which are typically stable enough to be isolated and detected as degradation products. The N-oxide functionality typically increases the reactivity of the aromatic ring. For example, the N-oxide functionality in pyridine N-oxide facilitates both electrophilic and nucleophilic substitution at the alpha and gamma positions (57). 

All these amination reactions show exclusive SNH substitution. There is hardly any indication for the formation of 3-nitropyridines, in which the chloro or methoxy group was replaced by an amino group, even when these leaving groups are present at the reactive a-position of the pyridine ring. It seems to be a characteristic feature of the oxidative amination... 

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