Nucleophiles pyridine reactivity with

Quite recently, the same research group compared the electrophilicity of 6-nitro-tetrazolo[l,5- ]pyridine and 6,8-dini-trotetrazolo[l,5- ]pyridine 11 with a series of electron-deficient aromatic and heteroaromatic compounds <2005JOC6242>. As reference nucleophiles, fV-methylpyrrole, indole, fV-methylindole, and some morpholino enamines were used. The reactivity of the electrophiles studied followed the linear-free energy relationship defined by Mayr et al. <2003ACR66>. 

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... 

A different behavior is found when strong nucleophiles are added to a polymerization of isobutene coinitiated with Lewis acids. When the concentration of nucleophile reaches that of Lewis acid, no polymerization is observed [5,91,268]. Quite often a precipitate, identified as a complex between Lewis acid and the nucleophile, is detected. This indicates that the complexed Lewis acid is no longer capable of ionization of the covalent species. A fractional negative order (-0.3) was reported in the polymerization of isobutene initiated by alkyl chloride/TiCL with added pyridines [268]. It is possible that a small amount of pyridine complexes with the Lewis acid, reduces its concentration, and thereby additionally shifts the equilibria from the more reactive dimeric to the less reactive monomeric TiCI4. Nevertheless, a small amount of nucleophile apparently has a beneficial effect, because polymers with lower polydispersities are formed. The plausible explanation of the role of nucleophiles in these systems will be offered in Section VILE.4. 

It has also been shown in radical substitution at the 2-position of a series of 4-substituted (CN, MeO, Me) protonated pyridines, that the cyclopropyl radical is the least nucleophilic of the cycloalkyl radicals This low nucleophilicity is consistent with the observed difficulty in oxidizing the cyclopropyl radical by Cu ". The lack of reactivity of the 2-phenylcyclopropyl radical, generated by the thermal decomposition of the 2-phenyl-cyclopropanepercarboxylic acid, towards the 0-0 peracid bond to yield 2-phenylcyclo-propanol is also in line with the radical s weak nucleophilicity However from a study of relative rates of hydrogen abstraction to olefin addition of the cyclopropyl radical to a variety of olefins (Table 7) Stefani and coworkers concluded that the cyclopropyl radical was decidedly nucleophilic. 

In Table 8 rates of nucleophilic reactions with p-nitrophenyl acetate in water are collected. It should be kept in mind that relative reactivities vary with solvent. For example, in aqueous dioxane the relative reactivity of pyridine, as compared with acetate, towards acetic anhydride drops by many powers often as the solvent becomes less aqueous (Koskikallio, 1963). In 50 %, 25 %, 8 %, 2 %, and 0-4 % aqueous dioxane the ratio of pyridine reactivity to acetate reactivity is 14,0-34, 9-5 x 10 , 2-4 X 10 and < 3 x 10 , respectively. 

Rate constants for the reaction of substituted pyridines with the 4-methoxystyrene radical cations have also been measured (Table 6). The bulky 2,6-di-tert-butyl pyridine reacts with the two methyl-substituted radical cations with rate constants of approximately 10 M s , but is substantially less reactive towards 4-methoxystyrene. This reaction has been attributed to deprotonation since electron transfer would be endergonic by -0.7 V and since the effects of methyl substitution at the P-carbon are opposite to those observed for other nucleophilic additions. 2,6-Dimethylpyridine also reacts with the two methyl-substituted radical cations with rate constants of 10 M s, but is approximately I order of magnitude more reactive towards the 4-methoxystyrene radical cation. The latter reaction must be nucleophilic addition since this radical cation cannot undergo deprotonalion. Product studies have confirmed that the reaction of 2,6-dimethylpyridine with the p-methyl-4-methoxystyrene radical cation is deprotonation. The major product of irradiation of a mixture of 1,4-dicyanobenzene, 4-methoxystyrene, and 2,6-dimethylpyridine is the rearranged tautomer, 3-(4-methoxyphenyljpropene, formed by a deprotonation, reduction, protonation sequence as shown in Eq. 19. By contrast to these... 

Other reactive bases can be used in this reaction. Pyridine reacts with phenyllithium at 100°C, for example, to give 2-phenylpyridine. This reaction is limited in scope because powerful nucleophiles are required and the reaction conditions can be harsh. Nonetheless, several interesting transformations are observed. Five-membered ring heterocycles are less prone to nucleophilic aromatic substitution, in part because the reparation of the requisite halogen-substituted derivatives can be difficult. 

The pyrazole molecule resembles both pyridine (the N(2)—C(3) part) and pyrrole (the N(l)—C(5)—C(4) part) and its reactivity reflects also this duality of behaviour. The pyridinic N-2 atom is susceptible to electrophilic attack (Section 4.04.2.1.3) and the pyrrolic N-1 atom is unreactive, but the N-1 proton can be removed by nucleophiles. However, N-2 is less nucleophilic than the pyridine nitrogen atom and N(1)H more acidic than the corresponding pyrrolic NH group. Electrophilic attack on C-4 is generally preferred, contrary to pyrrole which reacts often on C-2 (a attack). When position 3 is unsubstituted, powerful nucleophiles can abstract the proton with a concomitant ring opening of the anion. 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

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