Heterocyclic Compounds

Chapter Summary

Atoms other than carbon and hydrogen that appear in organic compounds are called heteroatoms. Cyclic organic compounds that contain one or more heteroatoms are called heterocycles. Heterocyclic compounds are the largest class of organic compounds and can be either aromatic (such as pyridine, pyrrole, and furan) or nonaromatic (such as piperidine, pyrrolidine, and tetrahydrofuran).

Pyridine is a six-membered heterocycle that has a structure isoelectronic with the aromatic hydrocarbon benzene. In pyridine, one of the –(CH)= units in benzene is replaced by an sp2-hybridized nitrogen [–(N:)=], and the nitrogen contributes one electron to the aromatic ring. Pyridine undergoes electrophilic aromatic substitution reactions at the 3-position, but at reaction rates much slower than benzene, partly because of the electron-withdrawing and deactivating effect of the nitrogen. Pyridine undergoes nucleophilic aromatic substitution upon treatment with strong nucleophiles like sodium amide and sodium methoxide. The reaction mechanism involves addition of the nucleophile to the electron-deficient pyridine followed by elimination of a leaving group. The nitrogen of pyridine is basic, and the nonbonded lone pair is protonated by mineral acids to give pyridinium salts. Catalytic hydrogenation of pyridine gives the nonaromatic six-membered heterocycle piperidine. Nicotine (from tobacco) and pyridoxine (vitamin B6) are two naturally occurring substituted pyridines.

Polycyclic aromatic heterocycles that contain pyridine rings fused with benzene rings include quinoline and isoquinoline. Quinine, used to treat malaria, is an example of a naturally occurring quinoline.

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy.

Pyrylium ions are six-membered heterocycles in which a positively charged sp2-hybridized oxygen replaces the nitrogen in pyridine. The pyrylium ring appears in many naturally occurring flower pigments.

Pyrrole, furan, and thiophene are five-membered aromatic heterocycles with one heteroatom. In pyrrole, the nitrogen is sp2-hybridized and contributes two electrons to the 6π aromatic ring. Furan and thiophene are isoelectronic with pyrrole, the [–(N:)=] unit being replaced by –(:O:)– and –(:S:)– units, respectively. Pyrrole, furan, and thiophene are electron-rich (there are six π electrons distributed over five atoms) and undergo electrophilic

Copyright © by Houghton Mifflin Company. All rights reserved. 233 234 Chapter 13 aromatic substitution at the 2-position with reaction rates much faster than benzene. Pyrrole rings form the building blocks of biologically important pigments called porphyrins. Hemoglobin and myoglobin (important in oxygen transport) and chlorophyll (important in photosynthesis) are examples of naturally occurring porphyrins. Furans are obtained commercially from furfural (furan-2-carbaldehyde), which is produced by heating corn cobs with strong acid.

Polycyclic aromatic heterocycles in which the 2- and 3-positions of a pyrrole are fused to a benzene ring are called indoles. The indole ring occurs in many medicinally important natural products, such as the neurotransmitter serotonin.

The azoles (oxazole, imidazole, and thiazole) are five-membered aromatic heterocycles that have two heteroatoms in the ring. One of the heteroatoms in each of these heterocycles is an sp2-hybridized nitrogen that contributes one electron to the 6π aromatic system and has a basic nonbonded lone pair. The other heteroatom (oxygen, nitrogen, or sulfur) contributes two electrons to the 6π system. The imidazole skeleton is present in the amino acid histidine. The thiazole ring occurs in thiamin (vitamin B1).

The purines are an important class of heterocycles in which an imidazole ring is fused to a pyrimidine ring. Uric acid (the main product of nitrogen metabolism in birds and reptiles), caffeine (present in coffee), and adenine and guanine (nitrogen bases present in the nucleic acids DNA and RNA) are examples of naturally occurring purines.

Reaction Summary

Reactions of Pyridine and Related Six-Membered Aromatic Heterocycles

1. Protonation

_ +HX X + N N H

X = Cl, Br, I, HSO4, and so forth

2. Electrophilic Aromatic Substitution

E +E+ +H+

N N .