23-1 amines chapter 23. 23-2 structure & classification amines are classified as: 1°, 2°, or,...

23-23-11

AminesAminesChapter 23Chapter 23

23-23-22

Structure & ClassificationStructure & Classification

Amines are classified as: • 1°, 2°, or , 3° amines:1°, 2°, or , 3° amines: Amines in which there are 1, 2, or

3 alkyl or aryl groups.

Methylamine(a 1° amine)

Dimethylamine(a 2° amine)

Trimethylamine(a 3° amine)

CH3-NH2 CH3-NH CH3-N

CH3 CH3

CH3: :

:

23-23-33


Amines are further divided into aliphatic, aromatic, and heterocyclic amines:• AliphaticAliphatic amine:amine: An amine in which nitrogen is bonded

only to alkyl groups.• Aromatic amine: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

::

:

23-23-44


• Heterocyclic amine: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 HN

H

23-23-66

Nomenclature Nomenclature

Aliphatic amines: replace the suffix -ee of the parent alkane by -amineamine.

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

2-Propanamine

NH2

NH2

NH2H2N

23-23-77

NomenclatureNomenclature

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

23-23-88


Among the various functional groups, -NH2 is one of the lowest in order of precedence.

COOHH2NOH

NH2

H2NOH

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

Amine vs alcohol

Amine vs acid

23-23-99


Common names for most aliphatic amines are derived by listing the alkyl groups bonded to nitrogen in one word ending with the suffix -amineamine.

CH3NH2 N

H

Et3NNH2

TriethylamineDicyclopentylamineMethylamine tert-Butylamine

23-23-1010


When four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine.

N

N NCl

Cl

tetramethylammonium chloride

1-ethyl-1-methylpiperidinium chloride

1-ethylpyridinium chlride

Cl

23-23-1111

Chirality of AminesChirality of Amines

• Consider the unshared pair of electrons on nitrogen as a fourth group, then the arrangement of groups around N is approximately tetrahedral.

• An amine with three different groups bonded to N is chiral and exists as a pair of enantiomers and, in principle, can be resolved.

23-23-1212


• In practice, however, they cannot be resolved because they undergo inversion, which converts one enantiomer to the other.

23-23-1313


• Pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved.

N

MeEt

N

MeEt

Cl- Cl-

S Enantiomer R Enantiomer

23-23-1414

Physical PropertiesPhysical 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) is less 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)

CH3CH3 CH3NH2 CH3OH

Using bp as an indication of H bonding

Increasing strength

23-23-1515

BasicityBasicity

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.

CH3NH3+ H2O CH3NH2 H3O+++

[CH3NH2][H3O+]

[CH3NH3+]

2.29 x 10-11==Ka pKa = 10.64

H

H

CH3-N H-O-HH

H

CH3-N-H O-H

Methylammonium hydroxideMethylamine

++

-

23-23-1616

BasicityBasicity

• Using values of pKa, we can compare the acidities of amine conjugate acids with other acids.

CH3NH2 CH3COOH CH3NH3+

CH3COO-

Keq = 7.6 x 105

+ +pKa 10.64pKa 4.76

(strongeracid)

(weakeracid)

pKeq = -5.88

23-23-1717

Basicity-Aliphatic AminesBasicity-Aliphatic Amines

Aliphatic Amines• note that pKa + pKb = 14

Tertiary Aminesdiethylaminedimethylamine

cyclohexylamineethylaminemethylamine

Secondary Amines

Primary AminesAmmonia

pKaStructureAmine

trimethylaminetriethylamine

9.26

10.6410.8110.66

10.7310.98

9.8110.75

pKb

4.74

3.36

3.343.19

3.273.02

4.193.25

CH3NH2

NH3

CH3CH2 NH2C6H1 1NH2

(CH3 )2NH(CH3 CH2)2 NH

(CH3 )3N(CH3 CH2)3 N

Stronger bases

23-23-1818

Basicity-Aromatic AminesBasicity-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

Weaker bases

Intermediate

23-23-1919


• Aromatic amines are considerably weaker bases than aliphatic amines.

NH2 H2O

H2ONH2

NH3+ OH-

NH3+ OH-

Cyclohexylamine

pKa = 4.63

Aniline

pKa = 10.66+

+

Cyclohexylammoniumhydroxide

Anilinium hydroxide

23-23-2020


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 NH H H H

H NH HH

+++

23-23-2121


• The greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with that of the sp3-hybridized carbon of an aliphatic amine.

And note the effect of substituents Electron-releasing groups, 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.

23-23-2222

Example: Basicity-Aromatic AminesExample: Basicity-Aromatic Amines

3-nitroaniline is a stronger base than 4-Nitroaniline.

NH2

O2N

NH2O2N

pKa 1.0pKa 2.474-Nitroaniline3-Nitroaniline

delocalization of the nitrogen lone pair onto the oxygen atoms of the nitro group

++

-

-

-

N NH2 NH2+N

O

O

O

O

Cannot do this kind of resonance in 3 nitroaniline

23-23-2323


Heterocyclic aromatic amines are weaker bases than heterocyclic aliphatic amines.

Piperidine ImidazolePyridinepKa 10.75 pKa 5.25 pKa 6.95

N NH

N

NH

23-23-2424


• 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 more tightly 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 not apart of the aromatic sextet

...

.. .

23-23-2525


Imidazole Which N lone pair is protonated? The one which is not part of the aromatic system.

This electron pair is not a part of the aromatic sextet

This electron pair is a partof the aromatic sextet

+ +

Aromaticity is maintained when imidazole is protonated

+

Imidazole Imidazolium ion

N

N

H

HN

N

H

H2 O OH-

:::

23-23-2626

Basicity-GuanidineBasicity-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.

:

C

NH2

NH2H2N H2N C NH2

NH2

C

NH2

NH2H2N

Three equivalent contributing structures

+ +

+

:

:

: :

:

++

Guanidine Guanidinium ion

C

NH

NH2H2N H2N C NH2

NH2+

H2O OH- pKa = 13.6

23-23-2727

Reaction with AcidsReaction with Acids

All amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts.

HO

HO

NH2

OH

HClH2O

HO

HO

NH3+ Cl-

OH

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

+

(R)-Norepinephrine(only slightly soluble in water)

23-23-2828

Reaction with acidsReaction with acids

Separation and purification of an amine and a neutral compound.

23-23-2929

PreparationPreparation

We have already covered these methods• nucleophilic ring opening of epoxides by ammonia and

amines.• addition of nitrogen nucleophiles to aldehydes and

ketones to form imines• reduction of imines to amines

• reduction of amides to amines by LiAlH4

• reduction of nitriles to a 1° amine

• nitration of arenes followed by reduction of the NO2 group to a 1° amine

23-23-3030

PreparationPreparation

Alkylation of ammonia and amines by SN2 substitution.

• Unfortunately, such alkylations give mixtures of products 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

CH3Br NH3 CH3NH3+ Br-

polyalkylations

23-23-3131

Preparation via AzidesPreparation via Azides

Alkylation of azide ion.

-- + + -

Azide ion (a good nucleophile)

An alkyl azide

N NN NN NRN3-

RN3:: :

: : : :

Ph CH2ClK

+ N3

-

Ph CH2N31. LiAlH4

2. H2OPh CH2NH2

Benzyl chloride Benzyl azide Benzylamine

Overall Alkyl Halide Alkyl amine

23-23-3232

Example: Preparation via AzidesExample: Preparation via Azides

• Alkylation of azide ion.

Cyclohexene

trans-2-Amino-cyclohexanol

(racemic)

1,2-Epoxy-cyclohexane

trans-2-Azido-cyclohexanol

(racemic)

ArCO3H 1. K+ N3-

2. H2O

1. LiAlH42. H2ON3

OH

NH2

OH

O

Note retention of configuration, trans trans

23-23-3333

Reaction with HNOReaction with HNO22

Nitrous acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl.

In its reactions with amines, nitrous acid: • Participates in proton-transfer reactions.• A source of the nitrosyl cation, NO+, a weak

electrophile.

HNO2 H2O H3O+

NO2-

+ pKa = 3.37+

23-23-3434

Reaction with HNOReaction with HNO22

NO+ is formed in the following way.• Step 1: Protonation of HONO.

• Step 2: Loss of H2O.

• 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)

23-23-3535

Tertiary Amines with HNOTertiary Amines with HNO22

• 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 participates in Electrophilic Aromatic Substitution.

Me2N1. NaNO2, HCl, 0-5°C

2. NaOH, H2ON=OMe2N

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

23-23-3636

Secondary Amines with HNOSecondary Amines with HNO22

• 2° Aliphatic and aromatic amines react with NO+ to give N-nitrosamines.

N-H HNO2 N-N=O H2O

Piperidine N-Nitrosopiperidine

+ +

carcinogens

N

H

N ON

H N=OH O

H

N

N=O

H O

H

H++

+ ++••

••

••••

••

• •

• •

• •••

• •• •

• •

• •

(1) (2)

Mechanism:

23-23-3737

RNHRNH22 with HNO with HNO22

1° aliphatic amines give a mixture of unrearranged and rearranged substitution and elimination products, all of which are produced by way of a diazonium ion and its loss of N2 to give a carbocation.

Diazonium ion:Diazonium ion: An RN2+ or ArN2

+ ion

23-23-3838

1° RNH1° RNH22 with HNO with HNO22

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

An N-nitrosamine

R-NH2 N R-N-N=OO+ : :

:

H: :

:

A diazotic acid

R-N=N-O-H

: : ::

A diazotic acid

R-N=N-O-H

: : ::

+

A diazonium ion

++

A carbocation

O-HNR-N

H

N NR N N

H+

-H2O

R+

•• ••

••

••

••

••

23-23-3939

1° RNH1° RNH22 with HNO with HNO22 (Aliphatic) (Aliphatic)

Aliphatic diazonium ions are unstable and lose N2 to give a carbocation which may:1. Lose a proton to give an alkene.

2. React with a nucleophile to give a substitution product.

3. Rearrange and then react by Steps 1 and/or 2.

(25%)

(5.2%)

(13.2%)

(25.9%) (10.6%)

0-5oC

NaNO2 , HClNH2OH

Cl

OH

+

+

23-23-4040

1° RNH1° RNH22 with HNO with HNO22

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

CH2NH2

OH

HNO2

O

H2O N2

+ + +

A-aminoalcohol Cycloheptanone

23-23-4141

Mechanism of Tiffeneau-DemjanovMechanism of Tiffeneau-Demjanov

• Reaction with NO+ gives a diazonium ion.

• Concerted loss of N2 and rearrangement followed by proton transfer gives the ketone.

:OH

CH2NH2HNO2

O-H

CH2 N N+

(A diazonium ion)

-N2

O

+ CH2

OH

CH2

O H+ proton transfer to H2O

A resonance-stabilized cation Cycloheptanone

:

:

: : :

:

:

:

Similar to pinacol rearrangement

23-23-4242

Pinacol Rearrangement: an example of Pinacol Rearrangement: an example of stabilization of a carbocation by an adjacent stabilization of a carbocation by an adjacent lone pair.lone pair.

Overall:

23-23-4343

MechanismMechanism

Reversible protonation.

Elimination of water to yield tertiary carbocation.

1,2 rearrangement to yield resonance stabilized cation.

Deprotonation.

This is a protonated

ketone!

23-23-4444

1° 1° Primary AminesPrimary Amines with HNO with HNO2 2 (Aromatic)(Aromatic)

The -N2+ group of an arenediazonium salt can be

replaced in a regioselective manner by these groups.

Ar-NH2HNO2

Ar-N2+ (-N2)

HCl, CuCl

H2O

HBF4

HBr, CuBr

KCN, CuCN

KI

H3PO2

Ar-I

Ar-F

Ar-H

Ar-Cl

Ar-Br

Ar-CN

Ar-OHSchiemannreaction

Sandmeyerreaction0-5°C

23-23-4545

1° ArNH1° ArNH22 with HNO with HNO22

A 1° aromatic amine converted to a phenol.

2-Bromo-4-methylaniline

2-Bromo-4-methylphenol

1. HNO2

2. H2O, heat

NH2

Br

CH3

OHBr

CH3

23-23-4646


Problem:Problem: What reagents and experimental conditions will bring about this conversion?

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

CH3 CH3

NO2

COOH

NO2

COOH

NH2

COOH

OH

23-23-4747


Problem:Problem: Show how to bring about each conversion.

NH2

CH3

ClCH3

CCH3

N

NH2

CH3

ClCl

CH2NH2

CH3

CH3

ClCl

(5)

(6) (7)

(8)

(9)

23-23-4848

Hofmann EliminationHofmann Elimination

Hofmann elimination:Hofmann elimination: Thermal decomposition of a quaternary ammonium hydroxide to give an alkene.• 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-

23-23-4949


• Step 2: Thermal decomposition of the 4° ammonium hydroxide.

(Cyclohexylmethyl)trimethyl- ammonium hydroxide

TrimethylamineMethylene-cyclohexane

++CH2 (CH3 )3N H2 O

160°+CH2-N-CH3

CH3

CH3

OH-

23-23-5050


Hofmann elimination is regioselective - the major product is the least substituted alkene.

Hofmann’s rule:Hofmann’s rule: Any -elimination that occurs preferentially to give the least substituted alkene as the major product is said to follow Hofmann’s rule.

CH3

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

heat+

23-23-5151


• The regioselectivity of Hofmann elimination is determined 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 (concertedelimination)

C C

H

N(CH3)3H

H H

CH

HC

H

CH3 CH2

HO-

N(CH3)3

HOH

CH3 CH2

23-23-5252

Cope EliminationCope Elimination

Cope elimination:Cope elimination: Thermal decomposition of an amine oxide.Step 1: Oxidation of a 3° amine gives an amine oxide.

Step 2: If the amine oxide has at least one -hydrogen, it undergoes 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

H 100-150°CCH2 (CH3)2NOH+

N,N-Dimethyl-hydroxylamine

Methylene-cyclohexane

+

-

23-23-5353

Cope EliminationCope 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

:

23-1 amines chapter 23. 23-2 structure & classification amines are classified as: 1°, 2°, or,...

Documents