C2 electrophilic substitution

Pyrrole s lone pair of electrons is the engine that propels many of its unique reactivities. Contrary to the indole where C3 electrophilic substitution takes 

Here is why the pyrrole ring prefers C2-electrophilic substitution. First of all, N1-electrophilic substitution is not favored because the positive charge would be localized on the nitrogen atom. On the other hand, C2-electrophilic substitution is favored over the C3-electrophilic substitution because the intermediate for the C2 substitution is more delocalized than that of the C3 substitution. This preference of more delocalization is reflected by the protonation as well. As shown in the previous section, 80% of the protonation occurs on the C2 position. 

The aforementioned regioisomer formation is showcased by bromination of pyrroles. The C2(a)-bromination is prevalent for bromination of the liV-Boc protected pyrrole.  

There are exceptions to the rule. For instance, when there is a bulky group on the nitrogen such as triisopropylsilyl group (TIPS), bromination occurs predominantly on the C3 (P) position instead of on the C2 (a) position.  

Depending on the reaction conditions, 1-methylpyrrole can be brominated at C2 with NBS (A -bromosuccinate) to give 2-bromo-l-methylpyrrole or at C3 with NBS and catalytic PBrs to give 3-bromo-l-methylpyrrole. Both reactions are essentially quantitative, but both bromides 

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In the last section, we saw many C2 halogenations. Depending on the substrates, C3 electrophilic substitutions do occur although often accompanying the C2 electrophilic substitutions. The C3 electrophilic substitutions generally take place more sluggishly and often at lower yields, although this is not always the case. 

Electrophilic substitutions on the indole ring overwhelmingly favor the C3 position. However, when the energy outcome is favorable, C2 electrophilic substitutions do occur, especially for intramolecular substitutions. For instance, in the synthesis of tadalafil (Cialis), the Pictet-Spengler reaction is used to prepare the cw-p-carboline where the C2 electrophilic substitution takes place. In the presence of trifluoroacetic acid (TFA), Z)-tryptophan methyl ester is condensed with piperonal. The C2-carbon of the indole adds to the resulting iminium ion to give a mixture of the cA-B-carboline and the... 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Draw resonance structures of the intermediate carbocations in the bromillation of naphthalene, and account for the fact that naphthalene undergoes electrophilic substitution at Cl rather than C2. 

Electrophilic substitutions normally occur at C2, the position next to the nitrogen, because reaction at this position leads to a more stable intermediate cation having three resonance forms, whereas reaction at C3 gives a less stable cation with only two resonance forms (Figure 24.6). 

According to Urbanski (Ref 6), . . Besides adding concentrated HN03 to olefms, true nitration of olefins thru electrophilic substitution can take place to yield nitroolefins.. . In 1878 Haitinger (Ref 1) found that nitration of isobutylene with anhydrous nitric add led to several products, among which was nitroisobutylene (CH3)C2=CHN02, in 10% yield... 

An example of electrophilic substitution on position C2 of the fused furan has been reported for 8H-furo[3,4-d]dibenz[ 7,/]azepine, which reacts with f-butyl hypochlorite to afford a mono chlorinated furan ring product (1995H431). 

The intramolecular C-acylation into position 4 becomes possible after hydrogenation of the C2—C3 bond in the indole nucleus. Thus, by the action of aluminum chloride, l-benzoyI-2,3-dihydroindo ylpropionyl chloride 197 is converted into pentahydrobenzo[crf]indolone 198 (54J A5256 56JA3087). Intramolecular electrophilic substitution is favored also by conjugation between a carbonyl or a nitrile group at the /3-substituent containing three carbon atoms and the indole nucleus. 

The intermediate 1,5-dicarbonyl compounds of type 24 (Scheme 1) can be constructed not only on the basis of meta-alkoxy-substituted benzyl ketones (C4 + Ci synthesis, Section II,C), but also under definite conditions starting from aryl ketones (C2 + C3 synthesis). Thus, in a molecule of acylveratrole derivatives of type 79, the excess of 7r-electron density due to the presence of two ortho-methoxy groups allows such compounds to be involved in electrophilic substitutions with benzoin (73URP2 74KGS1575). 

Electrophilic substitution of indole occurs preferentially at C3 metallation can activate C2. Complexation with Cr(CO)3 results in a marked preference for substitution at C4 steric factors can favor C7- over C4-substitution.3 Example ... 

Indole (2) undergoes electrophilic substitution preferentially at the b(C3)-position whereas pyrrole (1) reacts predominantly at the a(C2)-position [15]. The positional selectivity in these five-membered ring systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from 3 (for indole, 2) and a (for pyrrole, 1) are the more stabilized. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as Lewis acid catalysis, heating, or high pressure [15]. However, calculations of the frontier electron population for indole and pyrrole show that the HOMO of indole exhibits high electron density at the C3 while the HOMO of pyrrole is high at the C2 position [25-28] (Scheme 3). 

The intermediate derived from attack at the C2 position has greater delocalisation of the positive charge (mesomeric forms 2.28a,b,c) than that derived from attack at the C3 position (mesomeric forms 2.29a,b). As the charge is more extensively delocalised in the former, this intermediate is at lower energy. This in turn is reflected in a lower activation energy for this pathway and manifested in a selectivity for electrophilic substitution at the C2 position over the C3 position. The actual isomer ratio depends on the heterocycle, the electrophile, and the precise conditions, although in many cases such reactions are virtually regiospecific, and only the C2 substitution... 

The reaction proceeds by formation of the electrophilic Vilsmeier complex 2.30, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all undergo this formylation which is highly selective for the C2 position. 

Observe that electrophilic substitution occurs at the C3 position when both the C2 and C5 positions are blocked. 

A consequence of this delocalisation is that the lone pair is not available for protonation under moderately acidic conditions so, like pyrrole, indole is another weakly basic heterocycle. Another similarity to pyrrole is that being an electron-rich heterocycle indole easily undergoes aromatic electrophilic substitution, and is also rather unstable to oxidative (electron-loss) conditions. However, an important difference emerges here, in that whereas pyrrole preferentially reacts with electrophiles at the C2/C5 positions, indole substitutes selectively at the C3 position. The reasons for this will be discussed later. 

As an electron-rich heterocycle, indole easily undergoes electrophilic substitution. However whereas pyrrole reacts preferentially at the C2/C5 positions (see Chapter 2), indole reacts preferentially at the C3 position. 

When the nitrogen is blocked, deprotonation can occur at the C2 position, adjacent to the electronegative heteroatom. This offers a means of introducing electrophiles at this position, complementing the C3 selectivity shown by classical electrophilic substitution. For instance, alcohol 7.37 can be prepared in this way using ethylene oxide as the electrophile. 

There is neither a partial positive nor a partial negative charge on the two nonequivalent positions 1 and 2 of naphthalene, which are poised for electrophilic substitution. One might consequently predict that electrophiles react with naphthalene without regiocontrol. Furthermore, this should occur with the same reaction rate with which benzene reacts. Both predictions contradict the experimental results For example, naphthalene is brominated with a 99 1 selectivity in the 1-position in comparison to the 2-position. The bromination at Cl takes place 12,000 times faster and the bromination at C2 120 times faster than the bromination of benzene. 

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