Electrophilic attack at the a-position

The methyl groups on the pyridine ring result in a major difference in the reactivity of lutidines. In 3,5-lutidine the methyl groups act as electron donors tending to increase the stability of the tt-bonds, and activating the ring for electrophilic attack at the a-positions. The MOs in 3,5-lutidine show the it-levels pushed to lower energy... 

These cyclisations may proceed by direct electrophilic attack at the a-position, or by way of p-attack, then rearrangement. It may be significant that Mannich processes, as opposed to the alkylations discussed in Section 20.1.1.6, are reversible, which would allow a slower, direct a-substitution to provide the principal route to the a-substituted structure. 

There is still controversy as to whether such cyclisations proceed by direct electrophilic attack at the a-position, or whether by way of P-attack then rearrangement. It may be significant that Mannich processes, as opposed to the alkylations discussed in section 17.1.6, are reversible, which would allow a slower, direct a-substitution to provide the principal route to the a-substituted structure. It has been shown that tryptamines carrying a 2-carboxylic acid group, which can be conveniently prepared (section 17.16.2) but are not easily decarboxylated, undergo cyclising Mannich condensation with aldehydes and ketones, with loss of the carbon dioxide in a final step and under much milder conditions. ... 

The species (24) is a chiral homoenolate anion equivalent, and reacts with alkyl halides to give chiral j8-substituted aldehydes after hydrolysis. The anion (25) can also act as a homoenolate anion equivalent or, alternatively, as an acyl anion equivalent. For instance, reaction at -78 C results in electrophilic attack at the a-position (acylanion equivalent), whereas at 0°C y-attack is observed (homoenolate anion equivalent). 

Such calculations have been made also for pyrimidines of biological interest (B-60MI21302). That for uracil (5) is interesting in that a figure of -0.22 is assigned to the 5-position, compared with almost zero in pyrimidine this immediately explains the ease of electrophilic attack at the 5-position of uracil as well as the lack of nucleophilic activity at the same position. 

Aromatic character in isoxazoles has been studied from a number of viewpoints, and these studies indicate that although isoxazole may be formally considered an aromatic system, the disposition of the ring heteroatoms modifies this character to an appreciable extent. From a qualitative viewpoint, thermal stability and electrophilic attack at the 4-position may be considered consistent with an aromatic character. Furthermore, NMR chemical shifts of the ring protons are consistent with those of an aromatic compound. References related to these studies may be found in Section 4.16.2.3.4. 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

Pyridinones and quinolinones undergo electrophilic attack at the (3 -position (12,13) fairly easily and disubstitution is well known in the pyridine series. Pyridinones are more easily halogenated than benzene, but the highly acidic conditions used for nitration and sulfonation makes these less easy reactions. Electrophiles also attack at the oxygen (14), but this is considered as a substituent reaction and therefore will be dealt with in Chapter 2.06. 

While the acetylation of phenylferrocene also produces three similar acetyl-phenylferrocenes (III, IV, V R = CGH5) (as well as a very small amount of an isomer in which the phenyl group is acetylated), the site reactivities are different (108, 109). The ring bearing the phenyl substituent is deactivated compared to the unsubstituted ring. In contrast to alkylferrocenes, the 2-position is favored over the 3-position. It has been postulated that this is the result of enhanced resonance stabilization of the transition state in substitution involving electrophilic attack at the 2-position. 

The synthesis of the heteroarylcarboxylic acid chlorides is fraught with difficulties. When isolated, the acid chlorides are generally unstable and readily produce bisheteroaryl ketones (see Section 3.05.1.2.9). Using standard preparative procedures the increase in the acidity of the reaction medium can cause polymerization, whilst the addition of a base can result in the formation of compounds of the type (403) and (404). Attempts to prepare indole-2 -carboxylic acid chloride using thionyl chloride result in the isolation of sulfur-containing derivatives, which arise from electrophilic attack at the 3-position (64JOC178). 

The substituents in a benzene derivative may affect the rate of electrophilic attack at the ortho position by steric interaction and secondary bonding (e.g., hydrogen bonding or charge-transfer complexing) as well as by electrical influence. Therefore ortho substitution is less satisfactory. (See Section 2.2, p. 61 and Figure 2.2.)... 

Electrophilic attack on pyridine at the 2-position gives an unstable intermediate, with one of the resonance structures showing a positive charge and only six electrons on nitrogen. In contrast, electrophilic attack at the 3-position gives a more stable intermediate with the positive charge spread over three carbon atoms and not on nitrogen. 

The observation that carbenoids are capable of electrophilic attack at the 3-position of A -BOC-pyrrole may shed light on other carbenoid reactions that have stood out as rather unusual transformations. For example, a very useful [3- -2]-annulation between diazodimedone 1071 and ethyl 177-pyrrole-l-carboxylate leading to the tricyclic product 1072 was discovered (Scheme 208) <1995JOC2112>. It was proposed that the reactions occurred through initial cyclopropanation followed by ring opening of the pyrrolocyclopropane 1073 to a zwitterionic intermediate 1074. 

Thiophene and furan both are active to electrophilic attack in the a. positions and readily undergo acid exchange in those positions. For thiophene the ratio of rates of acid exchange128-130 at H-2 and H-3 is... 

Nitration of naphthalene gives 1-nitronaphthalene (12). Further substitution does not occur in the same ring and the main products of dinitration are 1,5- (13) and 1,8-dinitronaphthalenes (14). The initial nitro group deactivates that ring to further electrophilic substitution and attack at the a-positions of the other ring therefore takes place. 

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