Organic Chemistry

912 CHAPTER 21 More About Amines • Heterocyclic Compounds

Summary

Amines are compounds in which one or more of the hydro-
gens of ammonia have been replaced by R groups. Amines are
classified as primary, secondary, or tertiary, depending on
whether one, two, or three hydrogens of ammonia have been
replaced. Amines undergo amine inversionthrough a transi-
tion state in which the nitrogen becomes an nitrogen.
Some amines are heterocyclic compounds—cyclic
compounds in which one or more of the atoms of the ring is
an atom other than carbon. Heterocyclic rings are numbered
so that the heteroatomhas the lowest possible number. A
natural productis a compound synthesized by a plant or
an animal. Alkaloidsare natural products containing one or
more nitrogen heteroatoms and are found in the leaves,
bark, roots, or seeds of plants.
Because of the lone pair on the nitrogen, amines are both
bases and nucleophiles. Amines react as nucleophiles in nu-
cleophilic substitution reactions, in nucleophilic acyl sub-
stitution reactions, in nucleophilic addition–elimination
reactions, and in conjugate addition reactions.
Amines cannot undergo the substitution and elimination
reactions that alkyl halides undergo, because the leaving
groups of amines are too basic. Protonated amines also can-
not undergo the reactions that protonated alcohols and pro-
tonated ethers undergo. Amines are easily oxidized.
Saturated heterocycles containing five or more atoms have
physical and chemical properties typical of acyclic com-
pounds that contain the same heteroatom.
Quaternary ammonium hydroxides and amine oxides
undergo E2 elimination reactions known as Hofmann elim-
ination reactions and Cope elimination reactions, respec-
tively. In both reactions, the proton from the -carbon
bonded to the greater number of hydrogens is removed.

b

sp^3 sp^2

Quaternary ammonium salts are the most common phase

transfer catalysts.

Primary amines can be synthesized by means of a Gabriel

synthesis, by reduction of an alkyl azide or a nitrile, by

reductive amination, and by reduction of an amide.

Pyrrole,furan, and thiopheneare aromatic compounds

that undergo electrophilic aromatic substitution reactions

preferentially at C-2. These compounds are more reactive

than benzene toward electrophiles. When pyrrole is protonat-

ed, its aromaticity is destroyed. Pyrrole polymerizes in strong-

ly acidic solutions. Indole, benzofuran, and benzothiophene

are aromatic compounds that contain a five-membered aro-

matic ring fused to a benzene ring.

Replacing one of benzene’s carbons with a nitrogen forms

pyridine, an aromatic compound that undergoes electrophilic

aromatic substitution reactions at C-3 and nucleophilic aro-

matic substitution reactions at C-2 and C-4. Pyridine is less

reactive than benzene toward electrophilic aromatic substitu-

tion and more reactive toward nucleophilic aromatic sub-

stitution. Quinoline and isoquinoline are aromatic com-

pounds with both a benzene ring and a pyridine ring.

Imidazoleis the heterocyclic ring of the amino acid his-

tidine. The conjugate acid of imidazole has a of 6.8,

allowing it to exist in both the protonated and unprotonated

forms at physiological pH Nucleic acids

(DNA and RNA) contain substituted purinesand substitut-

ed pyrimidines. Hydroxypurines and hydroxypyrimidines

are more stable in the keto form. A porphyrin ring system

consists of four pyrrole rings joined by one-carbon bridges;

in hemoglobin and myoglobin, the four nitrogen atoms are

ligated to The metal atom in chlorophyll ais

and the metal atom in vitamin B 12 is Co^2 +.

Fe^2 +. Mg^2 +

1 pH=7.3 2.

pKa

PORPHYRIN, BILIRUBIN,

AND JAUNDICE

The average human turns over about 6 g of hemo-

globin each day. The protein portion (globin) and the iron are

reutilized, but the porphyrin ring is broken down. First it is re-

duced to biliverdin, a green compound, which is subsequently

reduced to bilirubin, a yellow compound. If more bilirubin is

formed than can be excreted by the liver, bilirubin accumulates

in the blood. When the concentration of bilirubin in the blood

reaches a certain level, bilirubin diffuses into the tissues, caus-

ing them to become yellow. This condition is known as

jaundice.

Summary of Reactions

1. Reaction of amines as nucleophiles (Section 21.4).
   a. In alkylation reactions:

R′

RBr RBr RBr

NH 2 R′ R′ NH

R R

NH 2

+

Br– R

R

R

NH

+ +

Br–

+ HBr

R′ N

R

R

R′ N

R

R

R

+ HBr

Br–