12.6 Heterocyclic Amines

As noted in Section 8.9 in connection with a discussion of aromaticity, a cyclic organic compound that contains atoms of two or more elements in its ring is a called a heterocycle. Heterocyclic amines are particularly common, and many have important biological properties. Pyridoxal phosphate, a coenzyme; sildenafil (Viagra), a well-known pharmaceutical; and heme, the oxygen carrier in blood, are a few examples.

Most heterocycles have the same chemistry as their open-chain counterparts. Lactones and acyclic esters behave similarly, lactams and acyclic amides behave similarly, and cyclic and acyclic ethers behave similarly. In certain cases, however, particularly when the ring is unsaturated, heterocycles have unique and interesting properties.

Pyrrole and Imidazole

Pyrrole, the simplest five-membered unsaturated heterocyclic amine, is obtained commercially by treatment of furan with ammonia over an alumina catalyst at 400 °C. Furan, the oxygen-containing analog of pyrrole, is obtained by acid-catalyzed dehydration of the five-carbon sugars found in oat hulls and corncobs.

Although pyrrole appears to be both an amine and a conjugated diene, its chemical properties are not consistent with either of these structural features. Unlike most other amines, pyrrole is not basic—the pK_a of the pyrrolinium ion is 0.4; unlike most other conjugated dienes, pyrrole undergoes electrophilic substitution reactions rather than additions. The reason for both of these properties, as noted in Section 8.9, is that pyrrole has six π electrons and is aromatic. Each of the four carbons contributes one π electron, and the sp²-hybridized nitrogen contributes two more from its lone pair.

Because the nitrogen lone pair is a part of the aromatic sextet, protonation on nitrogen would destroy the aromaticity of the ring. The nitrogen atom in pyrrole is therefore less electron-rich, less basic, and less nucleophilic than the nitrogen in an aliphatic amine. By the same token, the carbon atoms of pyrrole are more electron-rich and more nucleophilic than typical double-bond carbons. The pyrrole ring is therefore reactive toward electrophiles in the same way as enamines. Electrostatic potential maps show how the pyrrole nitrogen is electron-poor (less red) compared with the nitrogen in its saturated counterpart pyrrolidine, while the pyrrole carbon atoms are electron-rich (more red) compared with the carbons in 1,3-cyclopentadiene.

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin B1) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion.

Problem 12.11
Draw an orbital picture of thiazole. Assume that both the nitrogen and sulfur atoms are sp²-hybridized, and show the orbitals that the lone pairs occupy.

Pyridine

Pyridine is the nitrogen-containing heterocyclic analog of benzene. Like benzene, pyridine is a flat, aromatic molecule, with bond angles of 120° and C–C bond lengths of 139 pm, intermediate between typical single and double bonds. The five carbon atoms and the sp²-hybridized nitrogen atom each contribute one π electron to the aromatic sextet, and the lone-pair electrons occupy an sp² orbital in the plane of the ring (Section 8.9).

As shown previously in Table 12.1, pyridine (pK_a = 5.25) is a stronger base than pyrrole but a weaker base than the alkylamines. The diminished basicity of pyridine compared with that of alkylamines is due to the fact that the lone-pair electrons on the pyridine nitrogen are in an sp² orbital, while those on an alkylamine nitrogen are in an sp³ orbital. Because s orbitals have their maximum electron density at the nucleus but p orbitals have a node at the nucleus, electrons in an orbital with more s character are held more closely to the positively charged nucleus and are less available for bonding. As a result, the sp²-hybridized nitrogen atom (33% s character) in pyridine is less basic than the sp³-hybridized nitrogen in an alkylamine (25% s character).

Polycyclic Heterocycles

As we saw in Section 8.9, quinoline, isoquinoline, indole, and purine are common polycyclic heterocycles. The first three contain both a benzene ring and a heterocyclic aromatic ring, while purine contains two heterocyclic rings joined together. All four ring systems occur commonly in nature, and many compounds with these rings have pronounced physiological activity. The quinoline alkaloid quinine, for instance, is widely used as an antimalarial drug; tryptophan is a common amino acid; and the purine adenine is a constituent of nucleic acids.The chemistry of these polycyclic heterocycles is just what you might expect from a knowledge of the simpler heterocycles pyridine and pyrrole. Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms.

Problem 12.12
Which nitrogen atom in the hallucinogenic indole alkaloid N,N-dimethyltryptamine is more basic? Explain.

Problem 12.13
Indole reacts with electrophiles at C3 rather than at C2. Draw resonance forms of the intermediate cations resulting from reaction at C2 and C3, and explain the observed results.