Electrophilic Substitution at Carbon

The study of aromatic heterocyclic reactivity can be said to have begun with the results of electrophilic substitution processes - these were traditionally the means for the introduction of substitutents onto heterocylic rings. To a considerable extent that methodology has been superseded, especially for the introduction of carbon substituents, by methods relying on the formation of heteroaryllithium nucleophiles (section 2.6) and on palladium-catalysed processes (section 2.7). Nonetheless the reaction of heterocycles with electrophilic reagents is still extremely useful in many cases, particularly for electron-rich, five-membered heterocycles. 

Electrophilic substitution of aromatic (and heteroaromatic) molecules proceeds via a two-step sequence, initial addition (of X ) giving a positively charged intermediate (a cr-complex, or Wheland intermediate), then elimination (normally of H ), of which the former is usually the slower (rate-determining) step. Under most circumstances such substitutions are irreversible and the product ratio is determined by kinetic control. 

An initial broad division must be made in considering heteroaromatic electrophilic substitution, into those heterocycles which are basic and those which are not, for in the case of the former the interaction of nitrogen lone pair with the electrophile (cf. section 2.1), or indeed with any other electrophilic species in the proposed reaction 

Pyridines carrying activating substituents at C-2 are attacked at C-3/C-5, those with such groups at C-3 are attacked at C-2, and not at C-4, whilst those with substituents at C-4 undergo attack at C-3. 

Substituents which reduce the basicity of a pyridine nitrogen can also influence the susceptibility of the heterocycle to electrophilic susbtitution, in these cases by increasing the proportion of neutral (more reactive) pyridine present at equilibrium 2,6-dichloropyridine nitrates at C-3, as the free base, and only 10 times more slowly than 1,3-dichlorobenzene. As a rule-of-thumb it has been suggested that (i) pyridines with a pATa 1 will nitrate as cations, slowly unless strongly activated, and at an a or (3 position depending on the position of the substituent, (ii) weakly basic pyridines, pA a -2.5, nitrate as free bases, and at an a or / position depending on the position of the substituent.  

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

Bimolecular Electrophilic Substitutions at Carbon-Hydrogen Bonds... 

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],... 

The relatively low electron density at carbon, coupled with the possibility of protonation at nitrogen, makes electrophilic substitution at carbon difficult. A further problem is acid-catalyzed ring cleavage, particularly with alkyloxadiazoles. No examples of nitration or sulfonation of the oxadiazole ring have been reported and attempted brominations were unsuccessful. A low yield of 2-(2-furoyl)-5-phenyl-l,3,4-oxadiazole is obtained when 2-phenyl-l,3,4-oxadiazole is treated with 2-furoyl chloride in the presence of triethylamine (77LA159). 

Electrophilic substitution at nitrogen can occur in either ring, and the preference may depend on the nature of the substituents. Electrophilic substitution at carbon proceeds readily in the presence of electron-releasing substituents. 

Electrophilic substitution at nitrogen can occur in either ring depending on the nature of the substituents present. Electrophilic substitution at carbon proceeds readily in the presence of electron-releasing substituents. A wide variety of electrophiles have been studied. Mesoionic systems are readily substituted and cationic structures may become very reactive when conditions are chosen so as to promote intermediate formation of a pseudo-or anhydro-base. Sulfoxides are formed in the peracid oxidation of fused dihydrothiazoles. 

Electrophilic substitution at carbon is largely limited to the azine when this ring is activated by strongly electron-donating substituents. 

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. 

Electrophilic substitution at carbon, in simple pyridines at least, is very difficult, in contrast to the reactions of benzene - Eriedel-Crafts acylations, for example, do not occur at all with pyridines. This unreactivity can be traced to two factors ... 

In most cases, electrophilic substitution of pyridines occurs very much less readily than for the correspondingly substituted benzene. The main reason is that the electrophilic reagent, or a proton in the reaction medium, adds first to the pyridine nitrogen, generating a pyridinium cation, which is naturally very resistant to attack by an electrophile. When it does occur, electrophilic substitution at carbon must involve either highly unfavoured attack on a pyridinium cation or a relatively easier attack, but on a very low equilibrium concentration of uncharged free pyridine base. 

Electrophilic substitution at carbon can be effected much more readily with the three oxy-pyridines than with pyridine itself, and it occnrs ortho and para to the oxygen fnnction, as indicated below. Acid catalysed exchange of 4-pyridone in denterinm oxide, for example, gives 3,5-didenterio-4-pyridone, via C-protonation of the neutral pyridone. ... 

Reports of electrophilic substitution at carbon are limited to the 1,2,6-thiadiazine system and always take place at the 4-position <74JCS(Pl)2050,80JHC977). 

Electrophilic substitution at carbon, e.g. nitration and sulfonation, proceed very slowly. The action of chlorine or bromine leads to (3)5-chloro- or 3(5)-bromo-1,2,4-triazole by way of 1-halo intermediates ... 

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... 

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