Furan reactivity toward electrophiles

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

Phomactin A is the most challenging family member architecturally. The fragments that are most challenging are highlighted in Fig. 8.4. In Box-A, the highly sensitive hydrated furan is prone to dehydration under acidic or basic conditions, and any total synthesis almost certainly must save introduction of this fragment until the end game. Box-B relates to the strained and somewhat twisted electron-rich double bond. This trisubstituted olefin is extremely reactive toward electrophilic oxidants. 

Heteroaromatics very reactive toward electrophilic species, such as furan and pyrrole, are not suitable for homolytic aminations owing to their low stability under the reaction conditions. Thiophene, however, can be aminated, leading to 2-dialkylamino derivatives. ... 

Bromination The five-membered aromatic heterocycles are all more reactive toward electrophiles than benzene is, and the reactivity is similar to that of phenol. These compounds undergo electrophilic bromination. However, reaction rates vary considerably, and for pyrrole, furan and thiophene the rates are 5.6 x 10, 1.2 x 10 and 1.00, respectively. While unsubstituted five-membered aromatic heterocycles produce a mixture of bromo-derivatives, e.g. bromothiphenes, substituted heterocycles produce a single product. 

Like 1,3-azoles, due to the presence of a pyridine-like nitrogen atom in the ring, 1,2-azoles are also much less reactive towards electrophilic substitutions than furan, pyrrole or thiophene. However, 1,2-azoles undergo electrophilic substitutions under appropriate reaction conditions, and the main substitution takes place at the C-4 position, for example bromination of 1,2-azoles. Nitration and sulphonation of 1,2-azoles can also be carried out, but only under vigorous reaction conditions. 

Furan exhibits great reactivity towards electrophiles (71PMH(4)55, 71AHC(13)235) and the conditions under which these reactions are carried out require to be carefully controlled. 

It is convenient to consider heteroaromatic ligands in two classes - 7t-excessive, five membered rings typified by pyrrole, furan and thiophen, and TC-deficient six-membered rings typified by pyridine. The 7i-excessive heterocycles are usually extremely reactive towards electrophilic attack and, with the exception of thiophen, do not exhibit the chemical inertness often associated with aromatic benzene derivatives. Conversely, the TT-deficient heterocycles are extremely inert with respect to electrophilic attack. Paradoxically, it is the high reactivity of the five-membered rings and the inertness of the six-membered rings that give rise to common synthetic problems. The usual methods for the... 

The comparison among the reactivities towards electrophiles of the five-membered rings has been extended to tellurophen.318 In both the reactions examined (tin tetrachloride catalyzed acetylation and trifluoroacetylation), tellurophen exhibits a reactivity intermediate between those of selenophen and furan. 

The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated (see Chapter 5). 

Notice that the regioselectivity is the same as it was with pyrrole—the 2-position is more reactive than the 3-position in both cases. The product ketones are less reactive towards electrophiles than the starting heterocycles and deactivated furans can even be nitrated with the usual reagents used for benzene derivatives. Notice that reaction has occurred at the 5-position in spite of the presence of the ketone. The preference for 2- and 5-substitution is quite marked. 

Heteroaromatics have high reactivity toward electrophilic palladation and show good regioselectivity. Reactions with pyrrole,thiophene, furan, and indole have been reported (equation 3). The use of stoichiometric copper(II) ion gives a process catalytic in Pd. 

The chemistry of pyrrole, furan, and thiophene is similar to that of activated benzene rings. In general, however, the heterocydes are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and... 

In the above condensation resist designs, the phenolic resin offers a reaction site as well as base solubility. Self-condensation of polymeric furan derivatives has been utilized as an alternative crosslinking mechanism for aqueous base development (Fig. 126) [375]. The copolymer resist is based on poly[4-hydroxy-styrene-co-4-(3-furyl-3-hydroxypropyl)styrene], which was prepared by radical copolymerization of the acetyl-protected furan monomer with BOCST followed by base hydrolysis. The furan methanol residue, highly reactive toward electrophiles due to a mesomeric electron release from oxygen that facilitates the attack on the ring carbons, readily yields a stable carbocation upon acid treatment. Thus, the pendant furfuryl groups serve as both the latent electrophile and the nucleophile. Model reactions indicated that the furfuryl carbocation reacts more preferentially with the furan nucleus than the phenolic functionality. 

The C-H/C-X coupling between electron-rich or -neutral heteroarenes such as indoles, thiazoles, furans, and 1,3-azoles with aryl hahdes have been described frequently in the literature (see earlier discussion). However, the couphng of electron-deficient heteroarenes such as pyridines has remained Hmited due to their low reactivity toward electrophilic metalation as well as CMD processes. Furthermore, 2-metallaazines are generally unstable and incompatible with the reaction conditions, although examples of such cross-coupling reactions (C-M/C-X coupling) exist. 

It is known [446] that pyrrole is considerably more reactive toward electrophilic substitution than furan and even more reactive than thiophene. For instance, trifluo-roacetylation of 2-(2-furyl)- and 2-(2-thienyl)pyrroIes with trifluoroacetic acid anhydride proceeds selectively to form the corresponding 5-trifluoroacetyl-substituted pyrroles although under the same conditions, 2-(2-furyl)-N-vinylpyrrole is selectively acetylated at the furan ring [447]. 

Furan, thiophene, and pyrrole all have lower resonance energies than benzene (Table 12.5), and they are more reactive toward electrophiles. Even the simplest analysis should convince us that they are more electron rich than benzene—the six rt-electrons are distributed over only five atoms. 

Pyrrole, furan and thiophene undergo electrophilic substitution reactions. However, the reactivity of this reaction varies significantly among these heterocycles. The ease of electrophilic substitution is usually furan > pyrrole > thiophene > benzene. Clearly, all three heterocycles are more reactive than benzene towards electrophilic substitution. Electrophilic substitution generally occurs at C-2, i.e. the position next to the hetero-atom. 

A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not n-orbitals.5 For pyridine-N-oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 

Protiodeplumbylation (cleavage of PbR3 groups from aromatics) was used in the first demonstration that furan was more reactive than thiophene toward electrophiles (32RTC1054). 

---