Lecture 3: Five-membered Ring Heterocyclic Compounds PDF

Five-membered ring heterocyclic compounds 3rd Lecture Year 2 2nd Semester 2024 Dr Hasanain Ali Abbas Pharmaceutical Chemistry Department, Faculty of Pharmacy Jabir Ibn Hayyan University for Medical & Pharmaceutical Sciences...

Five-membered ring heterocyclic compounds 3rd Lecture Year 2 2nd Semester 2024 Dr Hasanain Ali Abbas Pharmaceutical Chemistry Department, Faculty of Pharmacy Jabir Ibn Hayyan University for Medical & Pharmaceutical Sciences 1  Structure of pyrrole, furan and thiophene The simplest of the five-membered heterocyclic compounds are pyrrole, furan, and thiophene, each of which contains a single hetero atom. The saturated derivatives are called pyrrolidine, tetrahydrofuran (THF), and thiophane, respectively. The bicyclic compounds made of a pyrrole, furan, or thiophene ring fused to a benzene ring are called indole (or isoindole), benzofuran, and benzothiophene, respectively. 2 Pyrrole, furan and thiophene are considered as aromatic compounds since they follow the Huckel’s aromaticity rules (4n+2 electron rule). The aromatic nature and extra-stability of these compounds can also be supported by the formation of different resonating structures as shown in below figures. 3  Bioactive Furans, Pyrroles and Thiophenes Ranitidine was the world's biggest-selling prescription drug. It is an H2-receptor antagonist and lowers stomach acid levels – used to treat stomach ulcers. Ketorolac is an analgesic and anti-inflammatory drug. Pyrantel is an anthelmintic agent and is used to treat worms in livestock. 4  Source of pyrrole, furan, and thiophene Pyrrole and thiophene are found in small amounts in coal tar. During the fractional distillation of coal tar, thiophene (b.p. 84) is collected along with the benzene (b.p, 80); as a result ordinary benzene contains about 0.5% of thiophene. Thiophene can be synthesized on an industrial scale by the high-temperature reaction between n-butane and sulfur. Pyrrole can be synthesized in a number of ways. For example: 5 The pyrrole ring is the basic unit of the porphyrin system, which occurs, for example, in haemoglobin and in chlorophyll. Furan is most readily prepared by decarbonylation (elimination of carbon monoxide) of furfural (furfuraldehyde), which in turn is made from pentosans. 6 Certain substituted pyrroles, furans, and thiophenes can be prepared from the parent heterocycles by substitution; most, however, are prepared from open-chain compounds by ring closure. For example: 7  Electrophilic substitution in pyrrole, furan and thiophene Like other aromatic compounds, these five-membered heterocycles are reactivate with electrophilic reagents to undergo electrophilic substitution reactions such as: nitration, halogenation, sulfonation, and Friedel-Crafts acylation. Whereas heterocyclic aromatic compounds tend to react by substitution, simple cycloalkenes generally give addition reactions. The aromatic five-membered heterocycles all undergo electrophilic substitution, with a general reactivity order: pyrrole >> furan > thiophene > benzene 8 Some examples are given in the below diagram. The exceptional reactivity of pyrrole is evidenced by its reaction with iodine, and formation of 2-acetylpyrrole by simply warming it with acetic anhydride (no catalyst). 9  Orientation of pyrrole, furan and thiophene There is a clear preference for substitution at the 2-position (α) of the ring, especially for furan and thiophene. Reactions of pyrrole require careful evaluation, since N-protonation destroys its aromatic character. Indeed, N- substitution of this 2º-amine is often carried out prior to subsequent reactions. For example, pyrrole reacts with acetic anhydride or acetyl chloride and triethyl amine to give N-acetylpyrrole. Consequently, the regioselectivity of pyrrole substitution is variable, as noted in the above diagram. An explanation for the general α-selectivity of these substitution reactions is apparent from the mechanism outlined below. 10 The intermediate formed by electrophile attack at C-2 is stabilized by charge delocalization to a greater degree than the intermediate from C-3 attack. 11 Functional substituents influence the substitution reactions of these heterocycles in much the same fashion as they do for benzene. Indeed, once one understands the ortho-para and meta-directing character of these substituents, their directing influence on heterocyclic ring substitution is not difficult to predict. Reactions 1 & 2 are 3-substituted thiophenes, the first by an electron donating substituent and the second by an electron withdrawing group. The third reaction has two substituents of different types in the 2 and 5- positions. 12