model pyrrole thiophene furan

These are 5-membered heterocycles whose heteroatoms are nitrogen, sulfur, and oxygen. They are aromatic systems (they comply with Hückel's rule), with thiophene being the one with the highest stabilization energy (more aromatic), followed by pyrrole, with furan being the least aromatic due to the strong electronegativity of oxygen that makes delocalization of oxygen difficult. the electronic cloud.

pyrrole thiophene furan




Pyrrole has an acid hydrogen on the nitrogen atom with pKa = 17. In the case of thiophene and furan, the acid hydrogens are located in position 2, although they have a much lower acidity than pyrrole.


Of the three heterocycles studied in this topic, pyrrole is the most reactive in electrophilic substitution. In acid media it polymerizes, nitra in the presence of nitric acid and acetic anhydride, sulfone with the pyridine-SO 3 complex, halogen in the presence of dilute halogen solutions at low temperature and gives the Vilsmeier and Mannich reactions.

Pyrrole is nitrated with nitric in acetic anhydride since the sulfonitric mixture produces polymerization.


a) Halogenation of pyrrole

To avoid polyhalogenation, work with diluted halogen and at a low temperature should be used. Another option is to use NBS or NCS.


The Vilsmeier formylation involves the reaction of heterocycles rich in electron density with dimethylformamide in the presence of phosphorus oxytrichloride.

The Mannich reaction allows placing the aminomethyl group on position 2 of the pyrrole.


It is possible to add electrophiles to the 3,4 position of the pyrrole by placing bulky groups on the nitrogen atom, so that the 2,5 positions are prevented. One of the most used groups is triisopropylsilyl.


Furan nitra with nitric acid in acetic anhydride, however, due to its poor aromaticity, is attacked by nucleophiles in the medium at its 5-position and requires a final stage of basic treatment or heating to restore aromaticity.

Stage 1. Generation of the electrophyte


Stage 2. Nucleophilic attack of furan on nitronium acetate


Although it is less reactive than pyrrole in S E , it still has problems with polyhalogenations, so it is required to use dilute halogens and at low temperatures. NBS and NCS can also be used.


a) Sulfonation of furan:

The furan sulfones with the SO 3 -Py complex

furan 01 sulfonation

d) Vilsmeier formulation

Furan reacts with dimethylformamide and phosphorus oxytrichloride, followed by basic hydrolysis, to form furan-2-carbaldehyde.
furan vilsmeier
The mechanism is analogous to that described for pyrrole.

The reagents and reaction conditions are similar to those used in pyrrole.

a) Nitration of thiophene

thiophene nitration

b) Halogenation of thiophene

thiophene halogenation

Pyrrole, thiophene and furan are not attacked by nucleophiles due to the strong electron density of the ring (excent p systems). Therefore, nucleophilic addition reactions, characteristic of p- deficient systems such as pyridine, quinoline and isoquinoline, are not observed.

The inability to stabilize the intermediate formed after nucleophilic attack makes this reaction impossible in 5-membered heterocycles. However, the presence of deactivating groups attached to the ring can make up for this deficiency, allowing the reaction.

nucleophilic substitution pyrrole thiophene furan

The nitro located in position 5 allows the delocalization of the charge generated during the addition stage.

The reaction of halogenated heterocycles with lithium organometallics produces the exchange of halogen for the metal, generating a new organometallic that allows attacking a wide variety of electrophiles.

heterocycle lithiation 01

The low aromaticity of furan allows it to participate in reactions that destroy the conjugation of the ring, such as: Diels-Alder, 1,3-dipolar, photochemical and kelotropic.

furan cycloaddition reactions

a) Leaving group near the ring

The ring expels the leaving groups that are in a neighboring position, this position being attacked by the nucleophiles in the middle.
derivatives pyrrole thiophene furan 01
The reaction takes place whether the chain is in position 2 or position 3.
derivatives pyrrole thiophene furan 02

Furan opens in aqueous acid media to form 1,4-dicarbonyls. The reaction follows the reverse steps of the Paal-Knorr synthesis.

furan opening

It consists of the reaction of a primary amine with a 3-ketoester forming an imine, which later tautomerizes to enamnin, attacking an a-haloketone. In a subsequent cyclization stage, pyrrole is obtained.

hantzsch pyrrole synthesis 01

Nitrile ylides react with alkynes, via the 1,3-dipolar reaction, to generate pyrroles

13 dipolar pyrrole