Organic Chemistry

4th Edition Paula Yurkanis Bruice

Chapter 21

More About Amines.

Heterocyclic

Compounds

Irene Lee

Case Western Reserve University

Cleveland, OH

©2004, Prentice Hall

Amines

• An amine is a base as well as a nucleophile

• Some amines are heterocyclic compounds

(or heterocycles)

• Most drugs, vitamins, and many other natural products

are heterocycles

• A natural product is a compound synthesized by a plant

or an animal

Alkaloids are natural products that contain one or

more nitrogen heteroatoms

More About Nomenclature of Heterocycles

Cyclic amines

N

CH2CH3

NH

CH3

NH

CH3

NHHN

azacylclopropane

aziridine

azacyclobutane

azetidine

3-methylazacyclopentane

3-methylpyrrolidine

2-methylazacyclohexane

2-methylpiperidine

N-ethylazacyclopentane

N-ethylpyrrolidine

Heterocycles with oxygen and sulfur heteroatoms

O S O

O O

O

O

oxacyclopropane

oxirane

ethylene oxide

thiacyclopropane

thiirane

oxacyclobutane

oxetane

oxacyclopentane

tetrahydrofuran

tetrahydropyran 1,4-dioxane

The lone-pair electrons on nitrogen allows an amine to

turn “inside out” rapidly at room temperature

Amines are the most common organic bases

Saturated heterocycles containing five or more atoms

have physical and chemical properties typical of their

acyclic analogs

Reactions of Amines

nucleophilic substitution reactions

CH3CH2Br + CH3NH2

Br

CH3CH2NHCH3 + HBrCH3CH2NH2CH3

nucleophilic acyl substitution reactions

CH3CH2

C

O

ClCH3NH2+ 2

CH3CH2

C

O

NHCH3

+ CH3NH3Cl

nucleophilic addition–elimination reactions

O HN+ N + H2O

conjugate addition reactions

CH3C CHCH

CH3 O

+ CH3NH

CH3

CH3C

CH3

CH2CH

NCH3

CH3

O

Relative Reactivity of Amine

The leaving group of a protonated amine cannot

dissociate to form a carbocation or be replaced by a

halide ion

RCH2F > RCH2OH ~ RCH2OCH3 > RCH2NH2

most reactive least reactive

HF H2O RCH2OH NH3

pKa = 3.2 pKa = 15.7 pKa = 15.5 pKa = 36

Reactions of Quaternary Ammonium Hydroxides

The leaving group of a quaternary ammonium ion has

about the same leaving tendency as a protonated amino

group

A Hofmann elimination is an E2 reaction

The hydrogen is removed from the -carbon bonded to

the most hydrogens

A strong base such as hydroxide ion must be used in the

elimination reaction

Quaternary ammonium salts are used as phase transfer

catalysts in facilitating the reactions between certain

ionic and organic reactants

Consider the reaction between sodium cyanide and an

alkyl halide …

Oxidation of Amines

R NH2 R NH OH R N O R N+

O-

Ooxd oxd oxd

R NH

R

+ H2O2 R N+

R

OH

H + OH- R N

R

OH

+ H2O

R N

R

+ H2O2 R N+

R

OH

R + OH- R N

R

O_

+ H2O

R R

a hydroxylamine a nitroso

compound

Amine Oxides Undergo a

Cope Elimination Reaction

The Gabriel Synthesis of Primary Amines

Other Methods for Synthesizing Amines

CH3CH2CH2CH2Br CH3CH2CH2CH2NH2

CH3CH2CH2CH2CH2NH2

1. NaCN, HCl

2. H2, Pd/C

1. N3-

2. H2, Pd/C

R

O

NH2

R

O

NHCH3

R

O

NCH3

CH3

1. LiALH4

2. H2O

1. LiALH4

2. H2O

1. LiALH4

2. H2O

RCH2NH2

RCH2NHCH3

RCH2NCH3

CH3

Reduction of Nitro Compounds

CH3CH2NO2 + H2

Pd/C

NO2 + H2 NH2

Pd/C

CH3CH2NH2

Reductive Amination

Secondary and tertiary amines can be prepared from

imines and enamines by reducing the imines or enamines

Aromatic Five-Membered Heterocycles

Pyrrole is an extremely weak base

The dipole moment in pyrrolidine (left) is attributed to

the electron-withdrawing property of the nitrogen atom

Pyrrole, furan, and thiophene undergo electrophilic

substitution preferentially at C-2

The relative reactivities of the five-membered-ring

heterocycles in Friedel–Crafts reaction

The resonance hybrid of pyrrole indicates that there is a

partial positive charge on the nitrogen

Pyrrole is unstable in strongly acid solution because the

protonated pyrrole polymerizes

Pyrrole’s acidity is increased due to its conjugated base

being stabilized by resonance

NH

indole

O

benzofuran

S

benzothiophene

Aromatic Six-Membered-Ring Heterocycles

The pyridinium ion is a stronger acid than a typical

ammonium ion

Pyridine Is a Tertiary Amine

Pyridine undergoes electrophilic aromatic substitution at

C-3

Pyridine undergoes nucleophilic aromatic substitution at

C-2 and C-4

Bromination and Oxidation of

Substituted Pyridine

Diazotization of Aminopyridine

The -hydrogens of alkyl substituents can be removed by

base to generate nucleophiles

Quinoline and isoquinoline are known as benzopyridines

Some Biologically Important Heterocycles

Imidazole

Porphyrin