Nucleophiles pyridine

The [Fe-Cp]-fragment does not only play the role of an additional steric element introducing planar chirality into the otherwise flat pyridine system. Substitution at the pyridine 2-position usually cuts the nucleophilicity of the nitrogen atom thus limiting the possibilities to achieve efficient chirality transfer using nucleophilic pyridine catalysts [84]. Ferrocene, however, functions as a strong electron donor (see Sect. 1) and thus restores the nucleophilicity impaired by substitution. 

The determination of the Concentrations in pyridine [N] which cause the coalescence of the signals of the diastereotopic groups of a 0.262 M solution methylneophyl-t-butyltin bromide (6) and of 0.332 M solution methylneophylphenyltin chloride (3) at 22 °C at respectively 60, 100 and 270 MHz shows12) that the k2 term is much smaller than the k3[N] term. From these results, it is clear that the inversion of the configuration of the metal atom of triorganotin halides is second-order in the nucleophile pyridine. An analogous rate equation has been found for the racemiza-tion of triorganosilicon halides 29), for which the activation entropy AS is about —50 e.u. Several mechanisms with increase of coordination number 30) can be proposed to account for this second order in the nucleophile 31) ... 

Pyridine has another useful attribnte, in that it behaves as a nncleophilic catalyst, forming an intermediate acylpyridinium ion, which then reacts with the nucleophile. Pyridine is more nucleophilic than the carboxylate anion, and the acylpyridinium ion has an excellent leaving group (pATa pyridinium 5.2). The reaction thus becomes a double nucleophilic substitution. 

Finally, before leaving this section, we shall consider the synthesis of pyridotriazine 5.32, a potential anti-fungal drug. This synthesis illustrates features of both electrophilic and nucleophilic pyridine chemistry. 

The situation is different in experiment 3 of Figure 2.12. There, both SN1 reactions are carried out as competitive reactions benzhydryl chloride heterolyzes (just as fast as before) in the presence of equal amounts of both amines. The benzhydryl cation is now intercepted faster by the more nucleophilic pyridine than by the less nucleophilic triethylamine. By far the major product is the pyridinium salt. 

Because the nitrogen atom is nucleophilic, pyridine can be oxidized to pyridine N-oxide with reagents such as m-CPBA or just H2C>2 in acetic acid. These N-oxides are stable dipolar species with the electrons on oxygen delocalized round the pyridine ring, raising the HOMO of the molecule. Reaction with electrophiles occurs at the 2- ( ortho ) and 4- ( para ) positions, chiefly at the 4-position to keep away from positively charged nitrogen. 

Spiroacylal 2 was designed under the rationale that the constraint of the carbonyl groups into a conformation in which overlap of their 7r-orbitals with the bent bonds of the cyclopropane is assured should dramatically increase the vulnerability of the cyclopropane toward nucleophilic attack.8 Experimental support for this notion is abundant.8 Spiroacylal 2 is considerably more reactive than 1,1-dicarbethoxycyclopropane in such reactions. For instance, reaction of 2 with piperidine occurs at room temperature. The corresponding reaction in the case of the diester is conducted at 110°C.5 Reactions with enolates also occur under mild conditions.8 Compound 2 reacts with the weak nucleophile pyridine at room temperature to give a betaine.8 An illustrative mechanism for the reaction of the acylal 2 with aniline to afford 2-oxo-l-phenyl-3-pyrrolidinecarboxylic acid (3) is... 

The reaction starts with loss of two electrons from the aromatic system of 39a this is stabilized by loss of a 2-butyl carbonium ion, which reacts with acetonitrile in a Ritter-type reaction, and by attack by the nucleophile pyridine. The second loss of two electrons maj occur before or after the ring closure. Similar internal substitution reactions are of potential value for the synthesis of heterocyclic compounds. 

Spiro compound 45 reacts with secondary cyclic amines to produce 536a (equation 188). On the other hand the spiro compound 45 in reaction with aniline gives a lactam (537) via sequential 1,5-addition and internal acylation. Even the weakly nucleophilic pyridine reacts with 45 to give the betaine 538 (equation 188) . 

Pyridine, 2-methylpyridine, and 2,4,6-collidinehave been added to avoid acidic conditions (to prevent secondary isomerizations) without deactivation of the silver salt by complexation or precipitation. In the absence of a nucleophile, pyridine forms allylic pyridinium salts and acetonitrile forms allylic amides. For example, formation of 5 and 6. ... 

The diene-Br2 complex is again in equilibrium with the reagents, and nucleophilic attack at carbon can be carried out either by the bromide of the ammonium bromide ion pair, formed at the moment of the electrophilic attack, or by the less nucleophilic pyridine added in excess in the reaction medium. It is noteworthy that this mechanism is characterized by a rate- and product-limiting nucleophilic step which should be quite insensitive to steric hindrance around the double bond. In agreement with a weak influence of the steric effects, pyridinium perbromide reacts in chloroform and tetrahydrofuran with substituted conjugated and non-conjugated dienes to give selectively (>95%) bromine addition to the more alkylated double bond (equation 44). 

Similarly, a wide range of nucleophiles have been shown to form four-coordinate adducts with Me3Si0S02CF3 (Nucleophile = pyridines, 2-pyridone, pyridine-N-oxide, phosphine oxides, ureas, imidazoles)108. Competition studies between Me3SiX and N-trimethylsilylimidazole led to the order of adduct formation109,110. 

Since tert-butylsulfone group acts as strong director of ort/io-lithiation, the Julia s method can be useful in the synthesis of various ori/jo-substituted biaryls. Finally, arenes such as pyridine do not require the presence of electron-withdrawing substituent for the reaction with nucleophiles. Pyridines react with aryllithiums at 2-position, which is electrophilic, via nucleophilic addition, to give the respective 2-arylpyridines (Chichibabin reaction manner). In this fashion, the reaction of lithiated ferrocene with pyridine results in formation of a-pyridylferrocene in 24% yield [49]. 

Nucleophilicity parameters, N and % for electrophile-nucleophile combination based on the Mayr equation ogk = Sj (N+E), were reported for highly nucleophilic pyridines bearing amino groups at carbons 3, 4, and 5, isothioureas," and thiocarboxylates, dithiocarbamate, and dithiocarbonate." Electrophilicity parameters E were reported for triarylmethyl cations with para and meta fluorine substituents," 1,3-diarylallyl cations," and aldehydes, imines, and enones." Nucleofugality parameters Nf and Sf for ionization based upon the Mayr equation logki = Sf(Ef + Nf) were reported for acetate in aqueous methanol" and chloride in aprotic solvents." The latter study also shows that common solvent parameters do not reliably predict ionization rates in aprotic solvents. Electrofugality parameters Ef were reported for triarylmethyl cations with para and meta fluorine substituents." ... 

For the reaction of the 3-pyridine aldimine 16e, the first equivalent of zinc chloride is coordinated to the more nucleophilic pyridine nitrogen and thus is inactivated. Only the second equivalent activates the imine. However, the zinc chloride coordinated to the more nucleophilic pyridine nitrogen, logically exposes more nucleophilic chlorine ligands for the interaction with the silyl dienol ether 19. Therefore, in this case the nucleophile 19 is introduced from the free back side of 16e (Formula C) and furnishes selectively the Mannich base 28 with opposite stereochemistry compared to the compounds 27. 

Kinetic Acidities Of Methylbenzenes. One electron oxidation of methylbenzenes affords very acidic cation radicals that undergo fast deprotonations by a series of pyridine bases (Py).25 26 One electron oxidation of the benzylic radical thus formed yields the benzylic cation that adds to the nucleophilic pyridine to give the pyridinium adduct. 25 26... 

The CpCo(CO)2 (10 mol %) catalyzed reaction of diyne 125 and cyanomesylate 126 under microwave heating (120 °C) delivered dehydrotylophorine (127) directly in 78% yield. Notably, during the course of this reaction cascade, the nonnucleophilic N-center of a nitrile is converted into a nucleophilic pyridine moiety that subsequently undergoes an intramolecular nucleophilic reaction with the tethered sulfonate leaving group. This facile tandem reaction has also been used in a synthetic approach to the spiroindolinone framework of the marine alkaloids citranin A and B [38]. 

Prompted by earlier results which indicated that the rate law for substitution of Cl in square-planar rran -[Pt(PEt3)2(R)Cl] (R = phenyl, jp-tolyl, or mesityl) complexes included an associative as well as the normal dissociative path only in the case of substitution by strong biphilic ligands (e.g. CN, SeCN ), Ricevuto et al. have re-examined the reaction with weakly nucleophilic pyridine in methanol ... 

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