Nucleophilic substitution resonance-stabilized intermediates

The Houben-Hoesch reaction proceeds via a straightforward electrophilic aromatic substitution mechanism. Following protonation or Lewis acid activation of the alkyl nitrile, nucleophilic attack by the electron-rich pyrrole selectively at C(2) produces the resonance stabilized intermediate 1. Elimination of H" reestablishes the aromaticity of the pyrrole, resulting in imine 2, which is rapidly hydrolyzed to produce the ketone 3. ... 

There are similarities between nucleophilic aromatic substitution (SnAt) and its more usual counterpart, electrophilic aromatic substitution. Each involves the formation of a resonance-stabilized intermediate, and each involves a temporary loss of aromaticity that is regained in the final step of the reaction. But the similarities are only so deep. The electrophilic reaction involves cationic intermediates the nucleophilic involves anionic intermediates. Use the differing effects of a nitro group, strongly deactivating in the electrophilic substitution and strongly activating in the nucleophilic substitution, to keep the two mechanisms distinct in your mind. 

Formaldehyde is protonated to give a resonance-stabilized cation that can serve as an electrophile in an electrophilic aromatic substitution reaction. Phenol functions as the nucleophile and attacks the electrophile, giving a resonance-stabilized intermediate (sigma complex). Water can then serve as a base and remove a proton from the sigma complex, thereby restoring aromaticity ... 

Unsymmetrically substituted dipyrromethanes are obtained from n-unsubstitued pyrroles and fl(-(bromomethyl)pyiToIes in hot acetic acid within a few minutes. These reaction conditions are relatively mild and the o-unsubstituted pyrrole may even bear an electron withdrawing carboxylic ester function. It is still sufficiently nucleophilic to substitute bromine or acetoxy groups on an a-pyrrolic methyl group. Hetero atoms in this position are extremely reactive leaving groups since the a-pyrrolylmethenium( = azafulvenium ) cation formed as an intermediate is highly resonance-stabilized. 

Two reaction mechanisms, such as SN1 and SN2 mechanisms, seem to be possible for explaining formations of 158a-c (Scheme 25). The former requires a resonance-stabilized indolyl cation 165 as an intermediate, while the latter indicates the presence of a transition state like 167. The introduction of a methoxy group into the 5 position of 165 should stabilize the corresponding cation 166, in which nucleophilic substitution on indole nitrogen would become a predominant pathway. 

Mechanism of nucleophilic aro-malic substitution. The reaction occurs in two steps and involves a resonance-stabilized carbanion intermediate. 

Nucleophilic substitutions on an aromatic ring proceed by the mechanism shown in Figure 16.17. The nucleophile first adds to the electron-deficient aryl halide, forming a resonance-stabilized negatively charged intermediate called a Meisenlieimer complex. Halide ion is then eliminated in the second step. 

Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group. The more such substituents there are, the faster the reaction. As shown in Figure 16.18, only ortho and para electron-withdrawing substituents stabilize the anion intermediate through resonance a meta substituent offers no such resonance stabilization. Thus, p-ch oronitrobenzene and o-chloronitrobenzene react with hydroxide ion at 130 °C to yield substitution products, but m-chloronitrobenzene is inert to OH-. 

Such an intermediate ean also stabilize itself by combining with a positive species. When it does, the reaction is nucleophilic addition to a C=C double bond (see Chapter 15). It is not surprising that with vinylie substrates addition and substitution often compete. For chloroquinones, where the charge is spread by resonance, tetrahedral intermediates have been isolated ... 

Reactivity factors in additions to carbon-hetero multiple bonds are similar to those for the tetrahedral mechanism of nucleophilic substitution. If A and/or B are electron-donating groups, rates are decreased. Electron-attracting substituents increase rates. This means that aldehydes are more reactive than ketones. Aryl groups are somewhat deactivating compared to alkyl, because of resonance that stabilizes the substrate molecule but is lost on going to the intermediate ... 

The effects of other substituent groups on the reactivity of ring halogen atoms are predictable. Electron-donating substituents make nucleophilic substitution more difficult while electron-withdrawing substituents facilitate the process. The effect of an electron-withdrawing substituent which is so positioned that it can participate in resonance stabilization of the intermediate adduct can be considerable. 

Electrophihc aromatic substitutions are unhke nucleophilic substitutions in that the large majority proceed by just one mechanism with respect to the substrate. In this mechanism, which we call the arenium ion mechanism, the electrophile (which can be viewed as a Lewis acid) is attacked by the 71-electrons of the aromatic ring (behaving as a Lewis base in most cases) in the first step. This reaction leads to formation of a new C—X bond and a new sp carbon in a positively charged intermediate called an arenium ion, where X is the electrophile. The positively charged intermediate (the arenium ion) is resonance stabilized, but not aromatic. Loss of a proton from the sp carbon that is adjacent to the positive carbon in the arenium ion, in what is effectively an El process (see p. 1487), is driven by rearomatization of the ring from the arenium ion to give the aromatic substitution product. A proton... 

Nucleophilic aromatic substitution on nitrochlorobenzenes. Oniy the ortho and para intermediate carbanions are resonance-stabilized, so only the ortho and para isomers undergo reaction. 

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