Reactivity in nucleophilic aromatic substitution

Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the... 

In a separate report, the regioselectivity and reactivity problems in the substitution of pyrimidines were avoided using 4,6-dichloro-5-nitropyrimi-dine as starting material,17 a very electron-poor heterocycle, which is highly reactive in nucleophilic aromatic substitutions. It reacts readily with the free amino group of the (trialkoxybenzhydrylamine) Rink linker on solid phase. This heterocycle could serve as a scaffold by itself and could also be used as a building block (precursor) to make other heterocycles such as purines. 

Leaving groups at C5 of 2-substituted 1,2,3-triazoles are predicted to be the most reactive in nucleophilic aromatic substitution reactions following an AE mechanism (see Section 1.4.2). Accordingly, chlorine at C5 of 360 could be replaced by strong nucleophiles like methanethiolate or methoxide to give 377 or 378. The unactivated 2-phenyl-4-chloro-l,2,3-triazole 380 (R=Ph) was inert toward these nucleophiles (1981JCS(P1)503) (Scheme 115). 

Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide the least reactive. 

In spite of the decrease in the basicity of BHFPA that should lower their reactivity in nucleophilic aromatic substitution, the ionomer synthesis was successful. Surprisingly, the water uptake dependence of the ionomers on lEC was found to be almost unaffected by the presence of the BHFPA repeat unit. This result, in agreement... 

There have been a large number of detailed studies, especially involving kinetic measurements, that have helped to establish the finer details of aromatic nucleophilic substitutions proceeding via the addition-elimination mechanism. Carbanions, alkoxides, and amines are all reactive in nucleophilic aromatic substitution and provide most of the cases in which this reaction has been used preparatively. Some examples are given in Scheme 8.8. 

I > Br > Cl > F. In nucleophilic aromatic substitution, the formation of the addition intermediate is usually the rate-determining step so the ease of C—X bond breaking does not affeet the rate. When this is the ease, the order of reactivity is often F > Cl > Br > I. This order is the result of the polar effeet of the halogen. The stronger bond dipoles assoeiated with the more eleetronegative halogens favor the addition step and thus inerease the overall rate of reaetion. 

The compound 1-fluoro-2,4-dinitrobenzene is exceedingly reactive toward nucleophilic aromatic substitution and was used in an imaginative way by Frederick Sanger (Section 27.11) in his determination of the structure of insulin. 

The most common types of aryl halides in nucleophilic aromatic substitutions are those that bear- o- or p-nitro substituents. Among other classes of reactive aryl halides, a few merit special consideration. One class includes highly fluorinated aromatic compounds such as hexafluorobenzene, which undergoes substitution of one of its fluorines on reaction with nucleophiles such as sodium methoxide. 

The difference in reactivity is not as much as is generally observed in nucleophilic aromatic substitution in solution by an addition-elimination mechanism (ref. 25). Substituents with electron withdrawing capabilities enhance the rate of the reaction therefore decabromobiphenyl ether reacts nearly 2 times faster than 1,2,3,4-tetrabromodibenzodioxin. 

Relative Reactivity of Pyridyl Derivatives in Nucleophilic Aromatic Substitutions... 

The aryl halide must be one that is reactive toward nucleophilic aromatic substitution by the addition-elimination mechanism. p-Fluoronitrobenzene is far more reactive than fluorobenzene. The reaction shown yields p-nitrophenyl phenyl ether in 92% yield. 

In nucleophilic as in electrophilic aromatic substitution, then, a substituent group affects reactivity by its ability to attract or release electrons in nucleophilic as in electrophilic aromatic substitution, a substituent group exerts its effect chiefly at the position ortho and para to it. The kind of effect that each group exerts, however, is exactly opposite to the kind of effect it exerts in electrophilic aromatic substitution. In nucleophilic aromatic substitution electron withdrawal causes activation, and electron release causes deactivation. 

Our interpretation of reactivity and orientation in nucleophilic aromatic substitution has been based on one all-important assumption that we have not yet justified displacement involves two steps, of which the first one is much slower than the second. 

Yet, in nucleophilic aromatic substitution, there is often very little difference in reactivity among the various halides and, more often than not, the fluoride— containing the carbon-halogen bond hardest to break—is the most reactive. If reactivity is independent of the strength of the carbon-halogen bond, we can only conclude that the reaction whose rate we are observing does not involve, breaking... 

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