Aminas e Heterociclicos Ch21MR

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Organic Chemistry

4thEditionPaula Yurkanis Bruice

Chapter 21

More About Amines.Heterocyclic

Compounds

Irene Lee

Case Western Reserve University

Cleveland, OH2004, Prentice Hall


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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


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Alkaloids are natural products that contain one or

more nitrogen heteroatoms


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More About Nomenclature of Heterocycles

Cyclic amines

N

CH2CH3

NH

CH3

NH

CH3

NHH

N

azacylclopropane

aziridine

azacyclobutane

azetidine

3-methylazacyclopentane

3-methylpyrrolidine

2-methylazacyclohexane

2-methylpiperidine

N-ethylazacyclopentane

N-ethylpyrrolidine


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Heterocycles with oxygen and sulfur heteroatoms

O S O

O O

O

O

oxacyclopropane

oxiraneethylene oxide

thiacyclopropane

thiirane

oxacyclobutane

oxetane

oxacyclopentane

tetrahydrofuran

tetrahydropyran 1,4-dioxane


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The lone-pair electrons on nitrogen allows an amine to

turn inside out rapidly at room temperature


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Amines are the most common organic bases

Saturated heterocycles containing five or more atoms

have physical and chemical properties typical of their

acyclic analogs


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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


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nucleophilic additionelimination reactions

O HN+ N + H2O

conjugate addition reactions

CH3C CHCH

CH3 O

+ CH3NH

CH3

CH3C

CH3

CH2CH

NCH3

CH3

O


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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


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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


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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


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Quaternary ammonium salts are used as phase transfer

catalysts in facilitating the reactions between certain

ionic and organic reactants


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Consider the reaction between sodium cyanide and an

alkyl halide


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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


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Amine Oxides Undergo a

Cope Elimination Reaction


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The Gabriel Synthesis of Primary Amines


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Other Methods for Synthesizing Amines

CH3CH2CH2CH2Br CH3CH2CH2CH2NH2

CH3CH2CH2CH2CH2NH2

1. NaCN, HCl

2. H2, Pd/C

1. N3-

2. H2, Pd/C


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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


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Reduction of Nitro Compounds

CH3CH2NO2 + H2

Pd/C

NO2 + H2 NH2

Pd/C

CH3CH2NH2


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Reductive Amination

Secondary and tertiary amines can be prepared from

imines and enamines by reducing the imines or enamines


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Aromatic Five-Membered Heterocycles

P l i t l k b


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Pyrrole is an extremely weak base


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The dipole moment in pyrrolidine (left) is attributed to

the electron-withdrawing property of the nitrogen atom


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Pyrrole, furan, and thiophene undergo electrophilic

substitution preferentially at C-2


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Th l ti ti iti f th fi b d i


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The relative reactivities of the five-membered-ring

heterocycles in FriedelCrafts reaction

Th h b id f l i di t th t th i


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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 basebeing stabilized by resonance


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NH

indole

O

benzofuran

S

benzothiophene


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Aromatic Six-Membered-Ring Heterocycles


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The pyridinium ion is a stronger acid than a typical

ammonium ion


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Pyridine Is a Tertiary Amine

Pyridine undergoes electrophilic aromatic substitution at


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Pyridine undergoes electrophilic aromatic substitution at

C-3

Pyridine undergoes nucleophilic aromatic substitution at


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Pyridine undergoes nucleophilic aromatic substitution at

C-2 and C-4

B i ti d O id ti f


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Bromination and Oxidation of

Substituted Pyridine


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The a-hydrogens of alkyl substituents can be removed by


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The a hydrogens of alkyl substituents can be removed by

base to generate nucleophiles

Quinoline and isoquinoline are known as benzopyridines


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Quinoline and isoquinoline are known as benzopyridines

S Bi l i ll I t t H t l


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Some Biologically Important Heterocycles

Imidazole


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Porphyrin


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Porphyrin

Aminas e Heterociclicos Ch21MR

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