Heterocyclic Compounds

Chapter Summary

Atoms other than 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 , , and ) or nonaromatic (such as , pyrrolidine, and ).

Pyridine is a six-membered heterocycle that has a structure isoelectronic with the aromatic hydrocarbon . In pyridine, one of the –(CH)= units in benzene is replaced by an sp2-hybridized [–(N:)=], and the nitrogen contributes one 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 like and sodium methoxide. The reaction mechanism involves addition of the to the electron-deficient pyridine followed by elimination of a leaving group. The nitrogen of pyridine is basic, and the nonbonded is protonated by mineral acids to give salts. Catalytic of pyridine gives the nonaromatic six-membered heterocycle piperidine. (from tobacco) and pyridoxine ( B6) are two naturally occurring substituted .

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

The (, , and ) are six-membered aromatic heterocycles that have two 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 include , which have four nitrogens in the rings. Naturally occurring derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy.

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

Pyrrole, furan, and are five-membered aromatic heterocycles with one heteroatom. In pyrrole, the nitrogen is sp2-hybridized and contributes two 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 ) 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. are obtained commercially from (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 . The ring occurs in many medicinally important natural products, such as the neurotransmitter serotonin.

The azoles (, , and ) 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 histidine. The thiazole ring occurs in thiamin (vitamin B1).

The are an important class of heterocycles in which an imidazole ring is fused to a pyrimidine ring. Uric acid (the main product of nitrogen in birds and reptiles), caffeine (present in ), 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


_ +HX X + N N H

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

2. Electrophilic Aromatic Substitution

E +E+ +H+

N N .

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