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
CH3

H N

NH
N H

azacylclopropane aziridine

azacyclobutane azetidine

3-methylazacyclopentane 3-methylpyrrolidine

N H

CH3

N CH2CH3

2-methylazacyclohexane 2-methylpiperidine

N-ethylazacyclopentane N-ethylpyrrolidine

Heterocycles with oxygen and sulfur heteroatoms

O
oxacyclopropane oxirane ethylene oxide

S
thiacyclopropane thiirane

oxacyclobutane oxetane
O

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

CH 3CH2Br

CH 3NH2

CH 3CH2NH 2CH 3 Br

CH 3CH2NHCH 3

+ HBr

nucleophilic acyl substitution reactions

O C CH 3CH2 Cl + 2 CH 3NH2 CH 3CH2 O C NHCH3 + CH 3NH3Cl

nucleophilic additionelimination reactions

HN

+ H2O

conjugate addition reactions

CH3 CH3C O CHCH + CH3NH CH3 CH3 CH3C NCH3 CH3 O CH2CH

Relative Reactivity of Amine

most reactive least reactive

RCH2F > RCH2OH ~ RCH2OCH3 > RCH2NH2

HF
pKa = 3.2

H2O
pKa = 15.7

RCH2OH
pKa = 15.5

NH3
pKa = 36

The leaving group of a protonated amine cannot dissociate to form a carbocation or be replaced by a halide ion

Reactions of Quaternary Ammonium Hydroxides

A Hofmann elimination is an E2 reaction

The leaving group of a quaternary ammonium ion has about the same leaving tendency as a protonated amino group

The hydrogen is removed from the b-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
oxd
R NH2 R NH OH

oxd
R N O

oxd
a nitroso compound
R N+

a hydroxylamine

O-

R R NH + H2O2 R

R N+ OH H + OHR

R N OH + H2O

R R N R + H2O2 R

R N+ OH
R + OH

R R N O_ + H2O R

Amine Oxides Undergo a Cope Elimination Reaction

The Gabriel Synthesis of Primary Amines

Other Methods for Synthesizing Amines

1. CH3CH2CH2CH2Br 1. NaCN, HCl 2. H2, Pd/C
N3

2. H2, Pd/C

CH3CH2CH2CH2NH2

CH3CH2CH2CH2CH2NH2

O 1. LiALH4 R O 1. LiALH4 R O 1. LiALH4 R NCH3 CH3 2. H2O RCH2NCH3 CH3 NHCH3 2. H2O RCH2NHCH3 NH2 2. H2O RCH2NH2

Reduction of Nitro Compounds

Pd/C CH3CH2NO2 + H 2 CH3CH2NH2

NO2

H 2

Pd/C NH2

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 FriedelCrafts 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

Pyrroles acidity is increased due to its conjugated base being stabilized by resonance

N H
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 a-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