Pyrroles, thiophenes, and furans

Under extreme conditions of acidity pyrrole is protonated, but at the C2 position. 

Note that protonation of the pyrrole nitrogen would lead to a non-aromatic cation. 

Pyrrole 2.1, thiophene 2.2, and furan 2.3, are five-membered ring heteroaromatic compounds containing one heteroatom. They derive their aromaticity from delocalisation of a lone pair of electrons from the 

The basis and extent of their aromaticity is discussed in Chapter 1. In summary, the capacity for the lone pair on a particular heteroatom to be delocalised is inversely related to the electronegativity of the heteroatom. For instance, furan is the least aromatic of the trio because oxygen has the greatest electronegativity and hence mesomeric representations 2.4b-e make relatively less of a contribution to the electronic structure of furan than they do in the cases of pyrrole and thiophene. The order of aromaticity is furan pyrrole thiophene. We shall see later how this variation in aromaticity affects the reactivities of these three related heterocycles. 

A small number of simple pyrroles such as 2.5 and 2.6 occur naturally. Far more important are the tetramic pyrrole derivatives (porphyrins) such as chlorophyll-a 2.7 and haem 2.8. 

---

There are examples of preferential arylation of Af-substituted pyrroles, thiophenes and furans in the 2-position. A preparatively useful reaction of this type is the o-nitrophenylation of thiophene (Scheme 40). A phase transfer catalytic technique has been recommended for this reaction (77TL1871). 

Perfluoroalkanoyl chlorides and anhydrides are also acylating agents Tri-fluoroacetic anhydride acylates a number of pyrroles, thiophenes, and furans without a catalyst [37, 38, 39] AzuUne can be diacylated without a catalyst in 12 h [40] (equation 26). 

Activation of pyrrole, thiophene, and furan molecules with pentaammineos-mium(n) 97CRV1953. 

Reactions of tc-excessive heteroaromatic compounds such as pyrroles, thiophenes and furans with carbenoids have been known for several years 6-10>u>. Recent activities were directed towards further synthetic applications of already known reactions, evaluation of the efficacy of novel catalysts and towards mechanistic insights. 

The data shown in Table 2 illustrate the general paucity of comparative toxicity data within an isosteric series of chemicals. In this Table a variety of toxic end-points observed for benzene and naphthalene have been compared with those of their simple heterocyclic analogues, and it is clear that it is almost impossible to derive chemical structure-biological activity relationships from the published literature for even such a simple series of compounds. Even basic estimates of mammalian toxicity such as LD50 values cannot be accurately compared due either to the absence of relevant data or the noncomparability of those available. Thus in a field where there are little comparative data on the relative toxicity to mammals of pyrrole, thiophene and furan for example, it is difficult to relate chemical structure to biological activity in historical heterocyclic poisons such as strychnine (3) and hemlock [active agent coniine (4)]. 

The reaction proceeds by formation of the electrophilic Vilsmeier complex 2.30, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all undergo this formylation which is highly selective for the C2 position. 

The relative reactivities of indole, 2- and N-methylindole, pyrrole, thiophene, and furan have been determined in alkylation by a benzenonium ion coordinated to iron tricarbonyl (73CC540). The effects of methyl substituents in pyrrole were determined in alkylation by 4-(7V,7V-dimethyl-amino)benzaldehyde [76JCS(P2)696]. In neither of these methods, nor in the alkylation of indole by aziridinium tetrafluoroborate [67AG(E)178], nor in self-alkylation of a X5-phosphorinyl tetrafluoroborate [73AG (E)753], is a catalyst required. 

Pyrroles, thiophenes, and furans from 1,4-dicarbonyl compounds... 

Oxygen-containing heterocycles are always less aromatic than their sulfur and nitrogen counterparts, e.g., imidazole thiazole >> oxazole and pyrazole > isothiazole > isoxazole. These trends follow those of pyrrole, thiophene and furan (Section 2.3.4.2). 1,2,3-Oxadiazole is unknown and all attempts to synthesize this compound have been unsuccessful. Although it is not the least aromatic of the oxadiazoles based on the HOMA index (cf. 1,3,4-oxadiazole), its instability can be attributed to easy isomerization to the acyclic valence tautomer (i.e., 85 - 86). 

Arylation of N-substituted pyrroles, thiophenes, and furans occurs preferentially in the 2-position, e.g., the o-nitrophenylation of thiophene by phase-transfer catalysis yields 204. 

Unsubstituted pyrrole, thiophene and furan are typical 7r-excessive heteroaromatics and readily react with electrophiles under mild conditions. The products of monosubstitution are mainly or solely 2-substituted derivatives. 

On electrophilic substitution of pyrrole, thiophene and furan derivatives carrying a carbonyl substituent at position 2, the orientation... 

---