Furan, protonation electrophilic substitution

Furans substituted with electron releasing groups usually undergo polymerization with mineral acids due to facile protonation at the 2-position. Aluminum chloride also causes resinification of furan but benzo[6 ]furan and compounds with electron withdrawing groups are, however, more stable. The reversion to type so characteristic of the electrophilic substitution of benzene is by no means prevalent in the chemistry of furan and benzo[6]furan and many apparent electrophilic substitutions in reality proceed by addition. 

Fusion of pyridine to a furan nucleus gives rise to six isomeric furopyridines (6-11 Scheme 1). Members of all these types are known. As is to be expected and as is shown even by simple HMO calculations (B-78MI31700, B-78MI31701, B-78MI31702), derivatives (6-9) of benzo[6]furan (4) are considerably more stable than the o-quinonoid isomers (10,11) derived from benzo[c]furan (5) (Tables 1 and 2). It is also to be noted that if super-delocalizabilities are considered as indices for reactivities, electrophilic substitution will occur in the furan nucleus both when considering the neutral heterocycles and the N-protonated species. 

A study using the CNDO/2 method was carried out for structure (17) and the results are shown in Figure 2 <80AP(313)1048>. Based on simple HMO calculations for a number of furopyridines using superdelocalizability to predict reactivity, electrophilic substitution is preferred on the furan ring for the neutral and protonated compounds. 

Many features of reactions of pyrrole, furan, thiophene and their derivatives bearing electron-releasing substituents with electrophiles are governed by their ready formation and the high stability of corresponding 2H-hetarenium ions, mainly a-C-protonation products like A (E = H). The reversible formation of such cr-complexes (Scheme 2, reaction 1) competes with acid-catalyzed oligomerization (reaction 2), which is practically irreversible and starts from the attack of an hetarenium cation on the neutral five-membered heterocycle analogously to the first step of electrophilic substitution. 

Scheme 8.104 A representation of a pathway for the substitution of an acetyl group for a proton at the C2 position (a to the oxygen) of furan under Lewis acid catalysis. Such electrophilic substitution reactions lend credence to the aromatic character of furan.

Protonation is the simplest form of electrophilic attack in furan it leads to polymerization since the ring can open to polyfunctional products or the protonated species can act as an electrophile and attack another furan molecule, so most work has to be on substituted furans. Even so, the naturally occurring trialkyl furan, petasalbin, is cleaved by so mild a reagent as silica164 ... 

The most important reactions involve electrophilic attack on ring carbon atoms, a wide variety of which are known for pyrroles, -furans and thiophenes. Most frequently, such electrophilic attack is followed by proton loss, resulting in overall substitution. 

Vinyl ethers and amines disclose little tendency to revert to type thus, the intermediate formed by reaction with an electrophilic reagent reacts further by adding a nucleophilic species to yield an addition compound cf the sequence (8) — (11). Thiophene and pyrrole have a high degree of aromatic character consequently the initial product formed by reaction of thiophene or pyrrole with an electrophilic species subsequently loses a proton to give a substituted compound cf the reaction sequence (12) — (15). Furan has less aromatic character and often reacts by overall addition as well as by substitution. In electrophilic addition, the first step is the same as for substitution, i.e. the formation of a tr-complex (e.g. 13), but instead of losing a proton this now adds a nucleophile. 

For benzo[b]furan and indole no such precise data are available, but it is possible to adduce some information from the various reactions described below. The positional reactivity orders for these molecules and also for benzo[b]thiophene, which have been calculated by various methods, are given in Table 8.1. In principle the ab initio calculations should be the more reliable, but neither the tt nor the (a + it) order is correct for benzo[6]thiophene, suggesting that these are incorrect for the other molecules also. The calculations using the STO-3G basis set certainly wrongly predict the site of most rapid protonation. Notably, only the Hiickel calculations give the correct order for benzo[b]thiophene and indeed they are usually the most reliable indicators for electrophilic aromatic substitution. 

The regioselective nudeophUic attack of the arylamine at the 2-methoxy-substituted iron complex salt is controlled by the methoxy group, which directs the arylamine to the para-position. Moreover, electrophilic attack takes place at the sterically less-hindered orfho-amino position. Iron-mediated oxidative cyclization of the resulting iron complex to the carbazole followed by proton-catalyzed aimulation of the furan ring provides 8-methoxyfurostifoline. Oxidation with 2,3-dich]oro-5,6-dicyano-l,4-benzoquinone (DDQ) to O-methylfurodausine-A followed by deavage of the methyl ether provides furoclausine-A (five steps, 9 % overall yidd). 

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