chapter23_amines

7/29/2019 Chapter23_Amines

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AminesChapter 23


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Structure & Classification

Amines are classified as

1, 2, or , 3 amines: amines in which 1, 2, or 3

hydrogens of NH3 are replaced by alkyl or aryl groups

Methylamine(a 1 amine)

Dimethylamine(a 2 amine)

Trimethylamine(a 3 amine)

CH3 - N H2 CH3 - N H CH3-N

CH3 CH3

CH3:

:

:


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Amines are further divided into aliphatic,

aromatic, and heterocyclic amines: aliphatic amine: an amine in which nitrogen is bonded

only to alkyl groups

aromatic amine: an amine in which nitrogen is bonded

to one or more aryl groups

Aniline(a 1 aromatic amine)

N-Methylaniline(a 2 aromatic amine)

Benzyldimethylamine(a 3 aliphatic amine)

NH2 N-H CH2-N-CH3

CH3 CH3

:

:

:


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heterocyclic amine: an amine in which nitrogen is one

of the atoms of a ring

PyrrolePiperidinePyrrolidine Pyridine

(heterocyclic aliphatic amines) (heterocyclic aromatic amines)

NN N

H H

N

H


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Example: classify each amino group by type

Caffein Morphine Heroin

O

O C6 H5

N

CH3

COOCH3

H

N

H

N

N

CH3

H

(b)

(S)-Coniine

(a)

Cocaine(S)-Nicotine

(c)


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Aliphatic amines: replace the suffix -eof the

parent alkane by -amine

1,6-Hexanediamine(S)-1-Phenyl-ethanamine

2-Propanamine

NH2

NH2

NH2H2 N


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Nomenclature

The IUPAC system retains the name aniline

3-Methoxyaniline(m-Anisidine)

4-Methylaniline(p-Toluidine)

Aniline 4-Nitroaniline(p-Nitroaniline)

NH2 NH2

CH3

OCH3

NH2

NO2

NH2


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Nomenclature

Among the various functional groups discussed

in the text, -NH2 is one of the lowest in order ofprecedence

COOHH2 NOHNH2

H2 NOH

4-Aminobenzoic acid2-Aminoethanol (S)-2-Amino-3-methyl-1-butanol


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Nomenclature

Common names for most aliphatic amines are

derived by listing the alkyl groups bonded tonitrogen in one word ending with the suffix -

amine

CH3 NH2 N

H

Et3 NNH2

TriethylamineDicyclopentylamineMethylamine tert-Butylamine


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Nomenclature

When four groups are bonded to nitrogen, the

compound is named as a salt of thecorresponding amine

Me4N

+Cl

-

NCH2 ( CH2 )1 2CH3

Cl-

Ph CH2NMe3 OH-

+

Benzyltrimethyl-ammoniumhydroxide

Tetramethyammonium

chloride

Tetradecylpyrid inium chloride(Cetylpyridinium chloride)


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Chirality of Amines

if we consider the unshared pair of electrons on

nitrogen as a fourth group, then the arrangement ofgroups around N is approximately tetrahedral

an amine with 3 different groups bonded to N is chiral

and exists as a pair of enantiomers and, in principle,

can be resolved

N

EtMe

HN

EtMe

H

the unshared

electron pair in

the fourth sp3

hybrid orbital

(S)-Ethylmethylamine (R)-Ethylmethylamine


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Chirality of Amines

in practice, however, they cannot be resolved because

they undergo pyramidal inversion, which converts oneenantiomer to the other

N

EtMe

HN Et

MeH

N

SEnantiomer REnantiomer

sp

3

sp3

sp2

Unhybridized

2porbital

Thetransitionstatehasaplaneof

symmetry;itisachiral


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Chirality of Amines

pyramidal inversion is not possible with quaternary

ammonium ions, and their salts can be resolved

N

MeEt

N

MeEt

Cl-

Cl-

SEnantiomer R Enantiomer


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Physical Properties

Amines are polar compounds, and both 1 and 2

amines form intermolecular hydrogen bonds

N-H- - -N hydrogen bonds are weaker than O-H- - -O

hydrogen bonds because the difference in

electronegativity between N and H (3.0 - 2.1 =0.9) isless than that between O and H (3.5 - 2.1 = 1.4)

bp (C) -6 .3 65.0-88.6

32.031.130.1MW (g/mol)

CH3 CH3 CH3 NH2 CH3 OH


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Basicity

All amines are weak bases, and aqueous

solutions of amines are basic

it is common to discuss their basicity by reference to

the acid ionization constant of the conjugate acid

H

H

CH3 -N H-O-H

H

H

CH3 -N-H O-H

Methylammonium h ydroxideMethylamine

++

-

CH3NH3+ H2 O CH3 NH2 H3 O

+++

[ CH3NH2 ] [H3 O+

]

[CH3 NH3+

]2.29 x 10

-11==Ka pKa = 10.64


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Basicity

using values of pKa, we can compare the acidities of

amine conjugate acids with other acids

CH3NH2 CH3 COOH CH3NH3+

CH3COO-

Ke q = 7.6 x 105

+ +

pKa 10.64pKa 4.76

(stronger

acid)

(weaker

acid)

pKeq = -5.88


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Basicity-Aliphatic Amines

Aliphatic Amines

CH3NH2

NH3

CH3CH2 NH2C6H1 1NH2

(CH3 ) 2NH

(CH3CH2 )2NH

(CH3 ) 3N(CH3CH2 )3N

Tertiary Amines

diethylamine

dimethylamine

cyclohexylamineethylamine

methylamine

Secondary Amines

Primary Amines

Ammonia

pKaStructureAmine

trimethylamine

triethylamine

9.26

10.64

10.8110.66

10.73

10.98

9.81

10.75

pKb

4.74

3.36

3.193.34

3.27

3.02

4.19

3.25


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Basicity-Aromatic Amines

NH2CH3

NH2Cl

NH2O2N

NH2

N

N

N

H

Heterocyclic Aromatic Amines

Aromatic Amines

StructureAmine

Aniline

4-Chloroaniline

4-Nitroaniline

4-Methylaniline

Pyridine

Imidazole

4.63

5.08

4.15

1.0

5.25

6.95

pKa of Conjugate Acid


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aromatic amines are considerably weaker bases than

aliphatic amines

NH2 H2 O

H2 ONH2

NH3+

OH-

NH3+

OH-

Cyclohexylamine

pKa = 4.63

Aniline

pKa = 10.66+

+

Cyclohexylammoniumhydroxide

Anilinium hydroxide


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Aromatic amines are weaker bases than aliphatic

amines because of two factors resonance stabilization of the free base, which is lost

on protonation

N

HH

H

HH

H

H

..

. .

. .

. .unhybridized 2p orbital of N

nitrogen is sp2 hybridized

N N N

H H H H

H N

H HH +++


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the greater electron-withdrawing inductive effect of the

sp2-hybridized carbon of an aromatic amine comparedwith the sp3-hybridized carbon of an aliphatic amine

also decreases basicity

Electron-releasing, such as alkyl groups,

increase the basicity of aromatic amines Electron-withdrawing groups, such as halogens,

the nitro group, and a carbonyl group decrease

the basicity of aromatic amines by a combination

of resonance and inductive effects


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4-nitroaniline is a weaker base than 3-nitroaniline

NH2

O2 N

NH2O2 N

pKa 1.0pKa 2.47

4-Nitroaniline3-Nitroaniline

de localization of the nitrog en

lone pair onto the oxyg en atom s

of the nitro group

++

-

-

-

N NH2 NH2+

N

O

O

O

O


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Heterocyclic aromatic amines are weaker bases

than heterocyclic aliphatic amines

Piperidine ImidazolePyridine

pKa

10.75 pKa

5.25 pKa 6.95

NN

H

N

N

H


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in pyridine, the unshared pair of electrons on N is not

part of the aromatic sextet

pyridine is a weaker base than heterocyclic aliphatic

amines because the free electron pair on N lies in an

sp2 hybrid orbital (33% s character) and is held moretightly to the nucleus than the free electron pair on N

in an sp3 hybrid orbital (25% s character)

:N

HH

H

HH

nitrogen is sp2 hybridized

an sp2 hybrid orbital; the electronpair in this orbital is n ot apart of the aromatic sextet

.

..

.

..


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Imidazole

This electron pairis not a part of thearomatic sextet

This electronpair is a partof the aromaticsextet

+ +

Aromaticity ismaintained whenimidazole is protonated

+

Imidazole Imidazolium ion

N

N

H

H

N

N

H

H2 O OH-

::

:


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Basicity-Guanidine

Guanidine is the strongest base among neutral

organic compounds

its basicity is due to the delocalization of the positive

charge over the three nitrogen atoms

:

CNH2

NH2H2 N H2 N C NH2

NH2

C

NH2

NH2H2 N

Thre e e quivale nt contributing structures

+ +

+

:

:

: :

:

++

Guanidine Guanidinium ion

C

NH

NH2H2 N H2 N C NH2

NH2+

H2 O OH- pKa = 13.6


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Reaction with Acids

All amines, whether soluble or insoluble in water,

react quantitatively with strong acids to formwater-soluble salts

HO

HO

NH2

OH

HCl

H2 OHO

HO

NH3+

Cl-

OH

(R)-Norepinephrine hydrochloride(a water-soluble salt)

+

(R)-Norepinephrine(only s lightly soluble in water)


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Preparation

We have already covered these methods

nucleophilic ring opening of epoxides by ammonia andamines (11.9B)

addition of nitrogen nucleophiles to aldehydes and

ketones to form imines (Section 16.8)

reduction of imines to amines (16.8A)

reduction of amides by LiAlH4(18.10B)

reduction of nitriles to a 1 amine (18.10C)

nitration of arene2 followed by reduction of the NO2

group to 1 amines (22.1B)


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Preparation

Alkylation of ammonia and amines by SN2

unfortunately, such alkylations give mixtures ofproducts through a series of proton transfer and

nucleophilic substitution reactions

CH3Br NH3

CH3NH3+Br

-(CH3 ) 2NH2

+Br

-(CH3 ) 3NH

+Br

-(CH3 ) 4N

+Br

-

+

+ + +

+ SN2

Methylammonium

bromide

CH3 Br NH3 CH3 NH 3+ Br-


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Preparation via Azides

Alkylation of azide ion

-- + + -

Azide ion(a good nucleophile )

An alkyl azide

N NN NN NRN3-

RN3:: :: : : :

Ph CH2ClK+ N3-

Ph CH2 N31. LiAlH4

2. H2OPh CH2 NH2

Benzyl chloride Benzyl azide Benzylamine


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Preparation via Azides

alkylation of azide ion

ArCO3H O2. H2O

N3

OH

1. K+ N3-

1. LiAlH42. H2O NH2

OH

Cyclohexene

trans-2-Amino-cyclohexanol

(racemic)

1,2-Epoxy-cyclohexane

(chiral)

trans-2-Azido-cyclohexanol

(racemic)


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Reaction with HNO2

Nitrous acid, a weak acid, is most commonly

prepared by treating NaNO2 with aqueous H2SO4or HCl

In its reactions with amines, nitrous acid

participates in proton-transfer reactions

is a source of the nitrosyl cation, NO+, a weak

electrophile

HNO2 H2O H3O+

NO2-

+ pKa = 3.37+

i i O


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Reaction with HNO2

NO+ is formed in the following way

we study the reactions of HNO2 with 1, 2, and 3

aliphatic and aromatic amines

H

H

N O+

OH

H+

OH N ONO OH

N O

+

+

+

+

The nitrosyl cation

(1) (2)

A i i h HNO


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Amines with HNO2

3 aliphatic amines, whether water-soluble or water-

insoluble, are protonated to form water-soluble salts 3 aromatic amines: NO+ is a weak electrophile and, as

such, participates in EAS

2 aliphatic and aromatic amines react with NO+ to give

N-nitrosoamines

Me2 N

1. NaNO2 , HCl, 0-5C

2. NaOH, H2ON=OMe2 N

N,N-Dimethyl-4-nitrosoanilineN,N-Dimethylaniline

N-H HNO2 N-N=O H2 O

Piperidine N-Nitrosopiperidine

+ +

A i i h HNO


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Amines with HNO2

Reaction of a 2 amine to give an N-nitrosamine

Step 1: reaction of the 2 amine (a nucleophile) withthe nitrosyl cation (an electrophile)

Step 2: proton transfer

N

H

N ON

H N=O

H O

H

N

N=O

H O

H

H++

+ +

+

(1) (2)

RNH ith HNO


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RNH2 with HNO2

1 aliphatic amines give a mixture of

unrearranged and rearranged substitution andelimination products, all of which are produced

by way of a diazonium ion and its loss of N2 to

give a carbocation

Diazonium ion: an RN2+ or ArN2

+ ion

1 RNH ith HNO


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1 RNH2 with HNO2

Formation of a diazonium ion

Step 1: reaction of a 1 amine with the nitrosyl cation

Step 2: protonation followed by loss of water

:

:+

keto-enoltautomerism

A 1 aliphatic

amine

A n N-nitrosamine

R-NH2 N R-N-N=OO

+ : ::

H

: ::

A diazotic acid

R-N= N-O -H

:

:

:

:

:

R-N=N-O-H

: : H+

:

N NR

O-HNR-N

H-H2O

R+

N NA diazotic acid

+

A diazonium ion

++

A carbo-cation

1 RNH ith HNO


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1 RNH2 with HNO2

Aliphatic diazonium ions are unstable and lose

N2 to give a carbocation which may1. lose a proton to give an alkene

2. react with a nucleophile to give a substitution product

3. rearrange and then react by 1 and/or 2

(25%)

(5.2%)

(13.2%)

(25.9%)(10.6%)

0-5oC

NaNO2,HClNH2OH

Cl

OH

+

+

1 RNH ith HNO


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1 RNH2 with HNO2

Tiffeneau-Demjanov reaction: treatment of a -aminoalcohol with HNO2 gives a ketone and N2

CH2 NH2

OH

HNO2

O

H2 O N2

+ + +

A-aminoalcohol Cycloheptanone

1 RNH ith HNO


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1 RNH2 with HNO2

reaction with NO+ gives a diazonium ion

concerted loss of N2 and rearrangement followed byproton transfer gives the ketone

:OH

CH2NH2HNO2

O-H

CH2 N N+

(A diazonium ion)

-N2

O

+ CH2

OH

CH2

O H+ proton transferto H2O

A resonance-stabilized cation Cycloheptanone

:

:

:

:

:

:

:

:

1 A NH ith HNO


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1 ArNH2 with HNO2

The -N2+ group of an arenediazonium salt can be

replaced in a regioselective manner by thesegroups

Ar-NH2HNO2

Ar-N2+ (-N2 )

HCl, CuCl

H2O

HBF4

HBr, CuBr

KCN, CuCN

KI

H3PO2Ar-I

Ar-F

Ar-H

Ar-Cl

Ar-Br

Ar-CN

Ar-OH

Schiemann

reaction

Sandmeyerreaction0-5C

1 A NH ith HNO


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1 ArNH2 with HNO2

A 1 aromatic amine can be converted to a

phenol

2-Bromo-4-methylaniline

2-Bromo-4-methylphenol

1. HNO2

2. H2O, heat

NH2Br

CH3

OH

Br

CH3

1 ArNH ith HNO


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1 ArNH2 with HNO2

Problem:what reagents and experimental conditions will

bring about this conversion?

(1) (2) (3) (4)

CH3 CH3

NO2

COOH

NO2

COOH

NH2

COOH

OH

1 ArNH with HNO


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1 ArNH2 with HNO2

Problem: Show how to bring about each

conversion

NH2

CH3

ClCH3

CCH3

N

NH2

CH3

ClCl

CH2 NH2

CH3

CH3

ClCl

(5)

(6)(7)

(8)

(9)

Hofmann Elimination


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Hofmann Elimination

Hofmann elimination: thermal decomposition of a

quaternary ammonium hydroxide to give analkene

Step 1: formation of a 4 ammonium hydroxide

(Cyclohexylmethyl)trimethyl-ammonium hydroxide

Silveroxide

(Cyclohexylmethyl)trimethyl-ammonium iodide

+

+ H2

OAg2O

AgI

CH2-N-CH3

CH3

CH3

I-

+

+CH2-N-CH3

CH3

CH3

OH-

Hofmann Elimination


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Hofmann Elimination

Step 2: thermal decomposition of the 4 ammonium

hydroxide

(Cyclohexylmethyl)trimethyl-ammonium hydroxide

Trime thylamineMethylene-

cyclohexane

++CH2 ( CH3 ) 3 N H2 O

160+CH2 -N-CH 3

CH3

CH3

OH-

Hofmann Elimination


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Hofmann Elimination

Hofmann elimination is regioselective - the major

product is the least substituted alkene

Hofmanns rule:any -elimination that occurspreferentially to give the least substituted alkene

as the major product is said to follow Hofmanns

rule

CH3

N(CH3 )3 OH- CH2 (CH3 )3N H2O++

heat+

Hofmann Elimination


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Hofmann Elimination

the regioselectivity of Hofmann elimination isdetermined largely by steric factors, namely the bulk of

the -NR3+ group

hydroxide ion preferentially approaches and removes

the least hindered hydrogen and, thus, gives the least

substituted alkene

bulky bases such as (CH3)3CO-K+ give largely Hofmann

elimination with haloalkanes

+

E2 reaction(concerted

elimination)

C C

H

N(CH3 ) 3H

H H

C H

HCH

CH3 CH2

HO -

N(CH3 ) 3

HOH

CH3 CH2

Cope Elimination


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Cope Elimination

Cope elimination:thermal decomposition of an

amine oxideStep 1: oxidation of a 3 amine gives an amine oxide

Step 2: if the amine oxide has at least one -hydrogen, itundergoes thermal decomposition to give an alkene

CH2 N-CH3

CH3

H2O2

O

CH3

CH2 N-CH3 H2O++

+

-

An amine oxide

O

CH3

CH2 N-CH3

H100-150C

CH2 (CH3 ) 2 NOH+

N,N-Dimethyl-hydroxylamine

Methylene-cyclohexane

+

-

Cope Elimination


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Cope Elimination

Cope elimination shows syn stereoselectivity but little

or no regioselectivity mechanism: a cyclic flow of electrons in a six-

membered transition state

:O

heat+

-

Transition state

an alkene

N,N-dimethyl-hydroxylamine

C C

H NCH3

CH3N

CH3

CH3

OH

C C

:


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AminesEnd Chapter 23

chapter23_amines

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