Electrophilic Substitution at Carbon Atom

In contrast to pyridines that are very resistant to electrophilic substitution at carbon without strong activating substituents, quinolines and isoquinolines are susceptible for substitution on the benzene ring. Following the dipole density described above, positions C5 and C8 are the only positions prone to 

Nitration takes place in the presence of fuming acid and concentrated sulfuric acid under mild conditions and mono-nitrations are occurred exclusively at C5 and C8 positions to provide usually a mixture of products for quinolines and C5 products for isoquinolines.  

Typical electrophilic reactions as Friedel-Craft acylation and Mannich reaction are not possible due to the nucleophilic nitrogen, which rapidly reacts with the electrophile. However, methods employing prior protection of nitrogen functionality are effective tricks to induce acylation on the desired direction. The preparation of antibiotic agent tipifamib highlights 

On the other hand, Mannich reaction of 5-chloro-8-hydroxy quinoline with formaldehyde and A //-diethylpropylenediamine proceeds according to the expected 7-substitution based on the prior substitution of positions C5 and C8 in a 5,8-disubstituted quinoline to afford the anti-malarial agent clamoxyquin.  

Quinolines and isoquinolines can also react with electrophiles at the pyridine side. This can be rationalized by a different reaction mechanism involving the prior introduction of a nucleophile in the heterocyclic quinoline/isoquinoline ring followed by an electrophilic substitution involving attack on the intermediate enamine. Notable is the electrophilic bromination of isoquinoline hydrobromide in a solvent like nitrobenzene that provides 81% yield of 4-bromoisoquinoline, in contrast to the bromination or chlorination of an isoquinoline-aluminum chloride complex that affords 78% of 5-bromoisoquinoline. Exhaustive bromination or chlorination under Lewis acid conditions usually yields mixtures of 5,8-halogenated isoquinolines along with 5,7,8-trisubstituted derivatives.  

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For general review on electrophilic substitution at carbon atom see (88BSB573 92H(33)1129 93AHC(57)291, 96KGS1535). 

Electrophilic substitutions at carbon, for example the reaction of an organometal-lic reagent with an electrophile, can occur either with retention [236, 238, 274, 275, 525, 529] or inversion [234, 471] at the nucleophilic carbon atom [57, 189, 522, 531, 532],... 

Little is reported on substitution at carbon atoms by electrophiles in these systems. As a result of their 7t-electron deficiency, azoloazines of the types discussed here are expected to be relatively unreactive toward electrophiles when electrophilic substitution occurs, it normally takes place at... 

Treatment of vinyl Sn, B, or Al compounds with BuLi results in effective addition of Bu to the metal to form a hypervalent anion such as 154. These are often referred to as ate complexes. The analogy is with the names of anions such as sulfate or carbonate. You are already familiar with the copper analogues, usually called cuprates. Lithium now replaces tin at the vinyl group 155 to form a vinyl-lithium derivative -156. The reaction is an electrophilic substitution at carbon - the lithium atom attacks the C-Sn bond and does so with retention of configuration. 

Unimolecular thermal and photochemical reactions Electrophilic attack at heteroatoms Electrophilic attack at carbon atoms Nucleophilic attack at carbon atoms Electrophilic attack on substituents Nucleophilic attack on substituents Nucleophilic substitution Synthesis... 

Aromatic amines are usually very reactive towards electrophilic reagents yielding derivatives substituted at carbon atoms. Reactions such as nitration and bromination can be applied to the amine as such, or to the amine previously protected at the nitrogen site. Although the derivatives from these reactions are useful for identification and possibly quantitative purposes, the site and stoichiometry of the substitution are specific for every system, and no generalisation can be made. Aryldiazonium salts undergo coupling reactions with aromatic amines to yield azo dyes, which can be used for detection and determination. In Table 12 some of the aryldiazonium salts used in analysis are listed. 

No example of electrophilic substitution at ring carbon atoms has been reported. 

Phospholes and analogs offer a wide variety of coordination modes and reactivity patterns, from the ti E) (E = P, As, Sb, Bi) through ri -dienic to ri -donor function, including numerous and different mixed coordination modes. Electrophilic substitution at the carbon atoms and nucleophilic properties of the phosphorus atom are well documented. In the ri -coordinated species, group V heteroles nearly acquire planarity and features of the ir-delocalized moieties (heterocymantrenes and -ferrocenes). 

The mechanism for the conversion of the A -oxide (94) to the o-methylaminophenylquinoxaline (96) involves an initial protonation of the A -oxide function. This enhances the electrophilic reactivity of the a-carbon atom which then effects an intramolecular electrophilic substitution at an ortho position of the anilide ring to give the spiro-lactam (98). Hydrolytic ring cleavage of (98) gives the acid (99), which undergoes ready dehydration and decarboxylation to (96), the availability of the cyclic transition state facilitating these processes. ... 

Volume 8 Volume 9 Volume 10 Volume 12 Volume 13 Proton Transfer Addition and Elimination Reactions of Aliphatic Compounds Ester Formation and Hydrolysis and Related Reactions Electrophilic Substitution at a Saturated Carbon Atom Reactions of Aromatic Compounds Section 5. POLYMERISATION REACTIONS (3 volumes)... 

The reactions in this chapter are arranged in order of leaving group hydrogen, metals, halogen, and carbon. Electrophilic substitutions at a nitrogen atom are treated last. 

The results are better with bromides or iodides DMSO not only enhances bimolecular nucleophilic displacements at carbon atoms but also increases electrophilic substitution. 

In contrast to the ease of reaction of ring nitrogen atoms in 77-deficient six-membered heterocycles with electrophiles, electrophilic heteroaromatic substitution at carbon of the unsubstituted compounds proceeds only under very drastic conditions and yields of products are usually very poor. This is also true with pyridinium, pyrylium and thiopyrylium salts,... 

Like other 7r-excessive heterocycles9 (e.g., azoles), the main reactions of azapentalenes are electrophilic substitutions at electron-rich centers (nitrogen or carbon atoms) in the molecule. 

If R is an alkyl group, reaction (1) leads to the familiar mechanism of nucleophilic substitution at saturated carbon whilst reaction (2) leads to an electrophilic substitution of saturated carbon. Of course for these mechanisms to be followed it is not necessary for a completely developed carbonium ion or carbanion to be formed, and both nucleophilic and electrophilic substitution at saturated carbon may proceed by mechanisms in which the carbon atom undergoing substitution has a carbonium ion character or a carbanion character respectively. 

When an electrophilic substitution at saturated carbon occurs, either a car-banion is liberated as such or, if no carbanion is actually formed, the carbon atom undergoing substitution has a certain amount of carbanion character . Thus a knowledge of the factors governing the formation and the stability of carbanions might be of help in the understanding of the mechanism of electrophilic substitution at saturated carbon. 

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