Thiophene, 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. 

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. 

The former procedure has been used for correlating the reactivities towards electrophiles of monosubstituted thiophenes. Good cr+ plots have been obtained. The p-values for the different reactions in thiophene and benzene have been tabulated (Table 2) (71AHC(13)235, 72IJS(C)(7)6l). 

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... 

Pyrrole is extremely reactive towards electrophiles while thiophene, the most aromatic of the trio, is much less reactive. At a very rough approximation, the reactivity of thiophene is of the order of a heteroatom-substituted benzene derivative such as phenol. Despite large differences in the rates of electrophilic substitutions there are some important aromatic substitution reactions common to all three heterocycles. 

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). 

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... 

Semiempirical methods assign a resonance energy for thiazole of 36.78 kcal mol (see Section 3.06.2), pointing out a marked similarity with thiophene. The aromatic character of thiazole is also demonstrated by its reactivity towards electrophilic substitutions (see Section 3.06.5). 

It is interesting to note that the pyridine ring in thienol 2,3-6 pyridine-A-oxide (53) is more reactive toward electrophiles than is the thiophene ring81 moreover, the orientation in nitration of this molecule depends on the reagent. 

All attempts to prepare the 5-sulfonyl chloride by reaction of 250 with die reagent under a variety of conditions failed. This result is different from the analogous chlorosulfonation of dibenzylideneacetone 237 when selective mono-chlorosulfonation was possible and may be due to the greater reactivity of the thiophene nucleus towards electrophilic attack. Benzylideneacetone 238 was condensed with aromatic aldehydes to yield the corresponding 1,5-diaryl-1,4-dien-3-ones 252. 

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. 

Additional acylation studies were also reported (24), (26). In the first case it is claimed that acylation of thiophene is achieved by means of HC104 and acetic anhydride affording a 65 % yield of 2-acetylthiophene. In the second paper Levine and coworkers reported that while 2,5-dimethylthiophene could be readily acetylated, 2,5-dichlorothiophene acetylated sluggishly. This is, however, readily explained, since the presence of chlorine atoms on the thiophene ring decreased its reactivity in electrophilic substitution reactions. In the case of methyl substitution, however, the 3 and 4 positions of the ring are activated toward electrophilic substitution by the inductive and hyperconjugative effects. Thus 2,5-dimethylthiophene was successfully acylated by the boron fluoride etherate method in high yield with three aliphatic anhydrides. 

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. 

---