Lecture 23- Amines

General

Organic ChemistryTwo credits

Second Semester 2009

King Saud bin Abdulaziz University for Health Science

Reference Book: Organic Chemistry: A Brief Course, by Robert C. Atkins and Francis A. CareyThird Edition

Instructor: Rabih O. Al-Kaysi, PhD.

Chapter 14Chapter 14

AminesAmines

Lecture 23

Preparation of Amines by Preparation of Amines by

ReductionReduction

almost any nitrogen-containing compound canalmost any nitrogen-containing compound canbe reduced to an amine, including:be reduced to an amine, including:

azidesazidesnitrilesnitrilesnitro-substituted benzene derivativesnitro-substituted benzene derivativesamidesamides

Preparation of Amines by ReductionPreparation of Amines by Reduction

SSNN2 reaction, followed by reduction, gives a 2 reaction, followed by reduction, gives a

primary alkylamine.primary alkylamine.

Synthesis of Amines via AzidesSynthesis of Amines via Azides CHCH22CHCH22BrBr

CHCH22CHCH22NN33

NaNaNN33

(74%)(74%) CHCH22CHCH22NNHH22

(89%)(89%)

1. LiAlH1. LiAlH44

2. H2. H22OO

azides may also bereduced by catalytichydrogenation

SSNN2 reaction, followed by reduction, gives a 2 reaction, followed by reduction, gives a

primary alkylamine.primary alkylamine.

Synthesis of Amines via NitrilesSynthesis of Amines via Nitriles

CHCH33CHCH22CHCH22CHCH22BrBrNaNaCCNN

(69%)(69%)

CHCH33CHCH22CHCH22CHCH22CCNN

CHCH33CHCH22CHCH22CHCH22CCHH22NNHH22

(56%)(56%)

HH22 (100 atm), Ni (100 atm), Ni

nitriles may also bereduced by lithiumaluminum hydride

Synthesis of Amines via NitroarenesSynthesis of Amines via Nitroarenes

HHNNOO33

(88-95%)(88-95%)

ClCl

ClCl NNOO22

HH22SOSO44

(95%)(95%)

1. Fe, HCl1. Fe, HCl

2. NaOH2. NaOH ClCl NNHH22

nitro groups may alsobe reduced with tin (Sn)+ HCl or by catalytichydrogenation

Synthesis of Amines via AmidesSynthesis of Amines via Amides

(86-89%)(86-89%)

COHCOH

OO1. SOCl1. SOCl22

2. (CH2. (CH33))22NNHH

CCNN(CH(CH33))22

OO

(88%)(88%)

1. LiAlH1. LiAlH44

2. H2. H22OO CHCH22NN(CH(CH33))22

only LiAlH4 is an

appropriate reducingagent for this reaction

Reductive AminationReductive Amination

Synthesis of Amines via Reductive AminationSynthesis of Amines via Reductive Amination

OOCC

RR

R'R'

++ NNHH33

fastfast

NNHHCC

RR

R'R'

++ HH22OO

HH22, Ni, Ni

NNHH22

RR

R'R' CC

HH

The imine undergoes hydrogenation fasterThe imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is than the aldehyde or ketone. An amine is the product.the product.

Example: Ammonia gives a primary amine.Example: Ammonia gives a primary amine. OO ++ NNHH33

HH

NNHH22

HH22, Ni, Ni

ethanolethanol

(80%)(80%)

via:via:

NNHH

Reactions of Amines:Reactions of Amines:

A Review and a PreviewA Review and a Preview

Reactions of AminesReactions of Amines

Reactions of amines almost always involve theReactions of amines almost always involve thenitrogen lone pair.nitrogen lone pair.

••••NN HH XX

as a base:as a base:

••••NN

CC OOas a nucleophile:as a nucleophile:

Reactions of AminesReactions of Amines

basicity basicity

reaction with aldehydes and ketones reaction with aldehydes and ketones

reaction with acyl chlorides reaction with acyl chlorides

Reactions already discussedReactions already discussed

Reactions of Amines with Alkyl Reactions of Amines with Alkyl

HalidesHalides

Reaction with Alkyl HalidesReaction with Alkyl Halides

Amines act as nucleophiles toward alkyl halides.Amines act as nucleophiles toward alkyl halides.

•••• XX++ ••••••••

••••

••••NN RR

HH

++ XX ••••••••

••••NN RR

HH

++ ––

++NN RR••••

HH++

Example: excess amineExample: excess amine NNHH22 ++ ClClCHCH22

NNHCHHCH22

(85-87%)(85-87%)

NaHCONaHCO33 90°C90°C

(4 mol)(4 mol) (1 mol)(1 mol)

Nitrosation of AlkylaminesNitrosation of Alkylamines

Nitrite Ion, Nitrous Acid, and Nitrosyl CationNitrite Ion, Nitrous Acid, and Nitrosyl Cation

HH++

––OO••••••••

••••NN OO

•••• ••••••••

OO•••• ••••

NN OO•••• ••••

••••HH

HH++

OO••••NN OO

•••• ••••

HH

HH

++••••++

••••NN OO

•••• ••••++OO ••••

HH

HH

••••

Nitrosyl Cation and NitrosationNitrosyl Cation and Nitrosation

++••••NN OO

•••• ••••

Nitrosyl Cation and NitrosationNitrosyl Cation and Nitrosation

++••••NN OO

•••• ••••++••••NN

NN••••NN OO

•••• ••••++

Nitrosation of Secondary AlkylaminesNitrosation of Secondary Alkylamines

++••••NN OO

•••• ••••••••NN

HH

++

NN••••NN OO

•••• ••••++

HH++

HH

++

NN••••NN OO

•••• •••••••• nitrosation of secondary nitrosation of secondary

amines gives an amines gives an NN--

nitroso aminenitroso amine

ExampleExample

(CH(CH33))22NNHH•••• NaNONaNO22, HCl, HCl

HH22OO(88-90%)(88-90%)

••••(CH(CH33))22NN

••••NN OO

•••• ••••

Some N-Nitroso AminesSome N-Nitroso Amines

NN-nitrosopyrrolidine-nitrosopyrrolidine(nitrite-cured bacon)(nitrite-cured bacon)

NN

NNOO

NN-nitrosonornicotine-nitrosonornicotine(tobacco smoke)(tobacco smoke)

NN

NNOONN

(CH(CH33))22NN NN OONN-nitrosodimethylamine-nitrosodimethylamine

(leather tanning)(leather tanning)

Nitrosation of Primary AlkylaminesNitrosation of Primary Alkylamines

++ analogous to analogous to

nitrosation of nitrosation of

secondary amines to secondary amines to

this pointthis point

++••••NN OO

•••• ••••••••NN

HH

HHRR

NN••••NN OO

•••• ••••++

HH

HHRR

++HH

++

NN••••NN OO

•••• ••••••••

RR

HH


NN••••NN OO

•••• ••••••••

RR

HH

HH++

NN••••NN OO

••••••••

RR

HH HH

++

this species reacts furtherthis species reacts further

••••NN

••••NN OO

••••••••

RR

HHHH

++

++

HHHH

++••••NN

••••NN OO••••

RR

HH


++

HH

••••NN••••NN OO••••

RR

HH

++NN NN ••••RR

HH

••••OO

HH

••••++nitrosation of a nitrosation of a

primary alkylamine primary alkylamine

gives an alkyl gives an alkyl

diazonium iondiazonium ion

process is called process is called

diazotizationdiazotization

Alkyl Diazonium Ions Alkyl Diazonium Ions

++NN NN ••••RR

alkyl diazonium ions alkyl diazonium ions

readily lose Nreadily lose N22 to to

give carbocationsgive carbocations

RR++ ++ NN NN ••••••••

There is no useful chemistry associated with the There is no useful chemistry associated with the nitrosation of tertiary alkylamines.nitrosation of tertiary alkylamines.

Nitrosation of Tertiary Alkylamines Nitrosation of Tertiary Alkylamines

••••NNRR

RR

RR

NN••••NN OO

•••• ••••++RR

RR

RR

Nitrosation of ArylaminesNitrosation of Arylamines

reaction that occurs is reaction that occurs is electrophilic aromatic substitutionelectrophilic aromatic substitution

Nitrosation of Tertiary ArylaminesNitrosation of Tertiary Arylamines NN(CH(CH22CHCH33))22

(95%)(95%)

1. NaNO1. NaNO22, HCl,, HCl,

H H22O, 8°CO, 8°C

2. HO2. HO––

NN(CH(CH22CHCH33))22

NNOO

similar to secondary alkylamines;similar to secondary alkylamines;

gives gives NN-nitroso amines-nitroso amines

Nitrosation of N-AlkylarylaminesNitrosation of N-Alkylarylamines

NaNONaNO22, HCl,, HCl,

HH22O, 10°CO, 10°C

NNHCHHCH33

(87-93%)(87-93%)

NNCHCH33

NN OO

Nitrosation of Primary Nitrosation of Primary ArylaminesArylamines

gives aryl diazonium ionsgives aryl diazonium ions

aryl diazonium ions are much more stable thanaryl diazonium ions are much more stable than

alkyl diazonium ionsalkyl diazonium ions

most aryl diazonium ions are stable under the most aryl diazonium ions are stable under the

conditions of their formation (0-10°C) conditions of their formation (0-10°C)

ArArNN NN++

RRNN NN++ fastfast

slowslow

RR++ ++ NN22

ArAr++ ++ NN22

Example:Example: (CH(CH33))22CHCH NNHH22

NaNONaNO22, H, H22SOSO44

HH22O, 0-5°CO, 0-5°C (CH(CH33))22CHCH NN NN

++HSOHSO44

––

Synthetic Origin of Aryl Diazonium SaltsSynthetic Origin of Aryl Diazonium Salts

ArAr HH

ArAr NNOO22

ArAr NNHH22

ArAr NN NN++

Synthetic TransformationsSynthetic Transformations

of Aryl Diazonium Saltsof Aryl Diazonium Salts

Transformations of Aryl Diazonium SaltsTransformations of Aryl Diazonium Salts

ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

Preparation of PhenolsPreparation of Phenols

ArAr NN NN++

ArAr OOHH

HH22OO, heat, heat

ExampleExample

2. H2. H22O, heatO, heat

(CH(CH33))22CHCH NNHH22

1. NaNO1. NaNO22, H, H22SOSO44

HH22O, 0-5°CO, 0-5°C (CH(CH33))22CHCH OOHH

(73%)(73%)


ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

Preparation of Aryl IodidesPreparation of Aryl Iodides

ArAr NN NN++

ArAr II

reaction of an aryl diazonium salt with reaction of an aryl diazonium salt with

potassium iodidepotassium iodide

KKII

ExampleExample

2. K2. KII, room temp., room temp.

1. NaNO1. NaNO22, HCl, HCl

HH22O, 0-5°CO, 0-5°C

(72-83%)(72-83%)

NNHH22

BrBr

II BrBr


ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

Preparation of Aryl FluoridesPreparation of Aryl Fluorides

ArAr NN NN++

ArAr FF

heat the tetrafluoroborate salt of a diazonium ion;heat the tetrafluoroborate salt of a diazonium ion;

process is called the Schiemann reactionprocess is called the Schiemann reaction

ExampleExample

(68%)(68%)

NNHH22 CCHCCH22CHCH33

OO

2. HBF2. HBF44


HH22O, 0-5°CO, 0-5°C

3. heat3. heat

FF CCHCCH22CHCH33

OO


ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

Preparation of Aryl Chlorides and Preparation of Aryl Chlorides and BromidesBromides

ArAr NN NN++

ArAr BrBrArAr ClCl

aryl chlorides and aryl bromides are prepared by heating aryl chlorides and aryl bromides are prepared by heating

a diazonium salt with copper(I) chloride or bromidea diazonium salt with copper(I) chloride or bromide

substitutions of diazonium salts that use copper(I) substitutions of diazonium salts that use copper(I)

halides are called halides are called SandmeyerSandmeyer reactionsreactions

ExampleExample

(89-95%)(89-95%)

2. Cu2. CuBrBr, heat, heat

1. NaNO1. NaNO22, HBr,, HBr,

HH22O, 0-10°CO, 0-10°CNNHH22

ClCl

BrBr ClCl


ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

Preparation of Aryl NitrilesPreparation of Aryl Nitriles

ArAr NN NN++

ArAr CNCN

aryl nitriles are prepared by heating a diazonium aryl nitriles are prepared by heating a diazonium

salt with copper(I) cyanidesalt with copper(I) cyanide

this is another type of Sandmeyer reactionthis is another type of Sandmeyer reaction

ExampleExample

(64-70%)(64-70%)

2. CuCN, heat2. CuCN, heat


HH22O, 0°CO, 0°CNNHH22

CHCH33

CNCN CHCH33


ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN


ArAr NN NN++

ArAr HH

hypophosphorous acid (Hhypophosphorous acid (H33POPO22) reduces diazonium ) reduces diazonium

salts; ethanol does the same thingsalts; ethanol does the same thing

this is called this is called reductive deaminationreductive deamination

ExampleExample

(70-75%)(70-75%)

NaNONaNO22, H, H22SOSO44,,

HH33POPO22

NNHH22

CHCH33 CHCH33

Value of Diazonium SaltsValue of Diazonium Salts

1) 1) allows introduction of substituents such as OH, F, allows introduction of substituents such as OH, F,

I, and CN on the ringI, and CN on the ring

2) 2) allows preparation of otherwise difficultly allows preparation of otherwise difficultly

accessible substitution patternsaccessible substitution patterns

ExampleExample BrBr

BrBrBrBr

NNHH22

BrBr

BrBr

BrBr

(74-77%)(74-77%)

NaNONaNO22, H, H22SOSO44,,

HH22O, CHO, CH33CHCH22OHOH

NNHH22 BrBr22

HH22OO

(100%)(100%)

Azo CouplingAzo Coupling

Azo CouplingAzo Coupling

Diazonium salts are weak electrophiles.Diazonium salts are weak electrophiles.

React with strongly activated aromatic compounds React with strongly activated aromatic compounds

by electrophilic aromatic substitution.by electrophilic aromatic substitution.

ArAr NN NN++

Ar'Ar' HH++ ArAr NN NN Ar'Ar'

an azo compoundan azo compound

Ar'Ar' must bear a strongly electron-releasing group must bear a strongly electron-releasing group such as OH, OR, or NR such as OH, OR, or NR22..

ExampleExample OHOH

++ CC66HH55NN NN++ OHOH

NN NCNC66HH55

ClCl––

Lecture 23- Amines

Documents

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n h n o n n

n n h2o

o h r n o n n

n n ki ar

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n h h r n h

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