chapter 21 amines

Chapter 21Chapter 21AminesAmines

21.121.1

Amine NomenclatureAmine Nomenclature

Alkylamine

N attached to alkyl group

Arylamine

N attached to aryl group

Primary, secondary, or tertiary

determined by number of carbon atoms directly attached to nitrogen

Classification of Amines

Two IUPAC styles

1) Analogous to alcohols: replace -e ending with -amine

2) Name alkyl group and attach -amineas a suffix

Nomenclature of Primary Alkylamines (RNH2)

Examples: some primary alkylamines

CH3CHCH2CH2CH3

NH2

(RNH2: one carbon directly attached to N)

CH3CH2NH2 NH2

ethylamine or ethanamine

cyclohexylamine orcyclohexanamine

1-methylbutylamine or2-pentanamine orpentan-2-amine

Name as derivatives of aniline.

Nomenclature of Primary Arylamines (ArNH2)

p-fluoroaniline or4-fluoroaniline

5-bromo-2-ethylaniline

NH2F

NH2

Br CH2CH3

Amino Groups as Substituents

p-aminobenzaldehyde

Amino groups rank below OH groups and higher oxidation states of carbon.

In such cases name the amino group as a substituent.

NH2HC

O

HOCH2CH2NH2

2-aminoethanol

Name as N-substituted derivatives of parent primary amine.

(N is a locant-it is not alphabetized, butis treated the same way as a numericallocant)

Parent amine is one with longest carbon chain.

Secondary and Tertiary Amines

Examples

CH3NHCH2CH3 N-methylethylamine NHCH2CH3

NO2

Cl

4-chloro-N-ethyl-3-nitroaniline

CH3

N

CH3

N,N-dimethylcycloheptylamine

A nitrogen with four substituents is positivelycharged and is named as a derivative of ammonium ion (NH4

+).

Ammonium Salts

CH3NH3

+Cl

–

methylammonium

chloride

+

N

CH3

H

CH2CH3 CF3CO2–

N-ethyl-N-methylcyclopentylammonium

trifluoroacetate

When all four atoms attached to N are carbon,the ion is called a quaternary ammonium ion andsalts that contain it are called quaternary ammonium salts.

Ammonium Salts

+

CH2 N

CH3

CH3

CH3 I–

benzyltrimethylammonium iodide

21.221.2

Structure and BondingStructure and Bonding

147 pm

106°112°

Alkylamines

Most prominent feature is high electrostaticpotential at nitrogen. Reactivity of nitrogen lonepair dominates properties of amines.

Alkylamines

Compare geometry at N of methylamine, aniline,and formamide.

sp3 sp2

Geometry at N

Pyramidal geometry at sp3-hybridized N in methylamine.

Planar geometry at sp2-hybridized N in formamide.

CO

NH2

H

C NH2

H

H

H

Compare geometry at N of methylamine, aniline,and formamide.

sp3 sp2

Geometry at N

Pyramidal geometry at sp3-hybridized N in methylamine.

Planar geometry at sp2-hybridized N in formamide.

Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of geometry at N.

sp3 sp2

Geometry at N

~125°180°

Note: This is not the same as the H—N—H bond angle.

Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of geometry at N.

sp3 sp2

Geometry at N

~125°180°

142.5°

Geometry at N in aniline is pyramidal; closer tomethylamine than to formamide.

Geometry at N

142.5°

Geometry at N

142.5°

Hybridization of N in aniline lies between sp3 and sp2.

Lone pair of N can be delocalized into ring best if N is sp2 and lone pair is in a p orbital.

Lone pair bound most strongly by N if pair is in an sp3 orbital of N, rather than p.

Actual hybridization is a compromise that maximizesbinding of lone pair.

Electrostatic Potential Maps of Aniline

Nonplanar geometry at N. Region of highestnegative potential is at N.

Planar geometry at N. High negative potential shared by N and ring.

Figure 21.2 (page 934)

21.321.3

Physical PropertiesPhysical Properties

Amines are more polar and have higher boiling points than alkanes; but are less polar andhave lower boiling points than alcohols.

Physical Properties

CH3CH2CH3 CH3CH2NH2 CH3CH2OH

dipolemoment ():

boiling point:

0 D 1.2 D 1.7 D

-42°C 17°C 78°C

Boiling points of isomeric amines decrease ingoing from primary to secondary to tertiary amines.

Primary amines have two hydrogens on N capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds.

Physical Properties

CH3CH2NHCH3CH3CH2CH2NH2 (CH3)3N

boilingpoint:

50°C 34°C 3°C

21.421.4

Basicity of AminesBasicity of Amines

Effect of Structure on Basicity

1. Alkylamines are slightly stronger bases than ammonia.

Amine Conj. Acid pKa

NH3 NH4+ 9.3

CH3CH2NH2 CH3CH2NH3+ 10.8

Table 21.1Basicity of Amines in Aqueous Solution

CH3CH2NH3+ is a weaker acid than NH4

+;therefore, CH3CH2NH2 is a stronger base than NH3.



2. Alkylamines differ very little in basicity.


NH3 NH4+ 9.3


(CH3CH2)2NH (CH3CH2)2NH2+ 11.1

(CH3CH2)3N (CH3CH2)3NH+ 10.8


Notice that the difference separating a primary,secondary, and tertiary amine is only 0.3 pK units.



2. Alkylamines differ very little in basicity.

3. Arylamines are much weaker bases thanammonia.


NH3 NH4+ 9.3


(CH3CH2)2NH (CH3CH2)2NH2+ 11.1

(CH3CH2)3N (CH3CH2)3NH+ 10.8

C6H5NH2 C6H5NH3+ 4.6


H2N•• Decreased Basicity of Arylamines

++H

N

H

H NH2 +•• +

H3N

pKa = 4.6

pKa =10.6

Strongeracid

Weakeracid

Strongerbase

Weakerbase

K = 106

+ H2N•• Decreased Basicity of Arylamines

+

H

H

N

H NH2 +•• +

H3N

Strongeracid

Weakeracid

When anilinium ion loses a proton, theresulting lone pair is delocalized into the ring.

+H

H

N

H

H2N•• Decreased Basicity of Arylamines

+ NH2 +•• +

H3N

Aniline is a weaker base because its lone pair is more strongly held.

Strongerbase

Weakerbase

Decreased Basicity of Arylamines

C6H5NH2 (C6H5)2NH (C6H5)3N

pKa of conjugate acid:

4.6 0.8 ~-5

Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

Effect of Substituents on Basicity of Arylamines

1. Alkyl groups on the ring increase basicity, butonly slightly (less than 1 pK unit).

X NH2

X pKa of conjugate acidH 4.6CH3 5.3

Effect of Substituents on Basicity of Arylamines

2. Electron withdrawing groups, especially orthoand/or para to amine group, decrease basicityand can have a large effect.

X NH2

X pKa of conjugate acidH 4.6CF3 3.5

O2N 1.0

p-Nitroaniline NH2

O

N

O

– ••••••

••

+

••

••

N

O

O

– ••••••

•• ••••–

NH2

+ +

Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization is lost on protonation.

Effect is Cumulative

Aniline is 3800 times more basic thanp-nitroaniline.

Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

Heterocyclic Amines N

H

••

N••

is more basic than

piperidine pyridinepKa of conjugate acid:

11.2


5.2

(an alkylamine)(resembles anarylamine in

basicity)

Heterocyclic Amines N••

is more basic than

imidazole pyridinepKa of conjugate acid:

7.0


5.2

N HN••

••

Imidazole N HN••

••

Which nitrogen is protonated in imidazole?

H+ H+ N HN ••H

+ +

N HN••

H

Imidazole N HN••

••

Protonation in the direction shown gives a stabilized ion.

H+ N HNH

+ ••

N HNH

••+

21.521.5

Tetraalkylammonium SaltsTetraalkylammonium Salts

as Phase-Transfer Catalystsas Phase-Transfer Catalysts

Phase-Transfer Catalysis

Phase-transfer agents promote the solubility ofionic substances in nonpolar solvents. Theytransfer the ionic substance from an aqueousphase to a non-aqueous one.

Phase-transfer agents increase the rates ofreactions involving anions. The anion is relativelyunsolvated and very reactive in nonpolar mediacompared to water or alcohols.

+


Quaternary ammonium salts are phase-transfercatalysts. They are soluble in nonpolar solvents.

NH3C

CH2CH2CH2CH2CH2CH2CH2CH3



Cl–

Methyltrioctylammonium chloride


Quaternary ammonium salts are phase-transfercatalysts. They are soluble in nonpolar solvents.

Cl–

Benzyltriethylammonium chloride

+N

CH2CH3

CH2CH3

CH2CH3

Example

The SN2 reaction of sodium cyanide with butyl

bromide occurs much faster when benzyl-triethylammonium chloride is present than whenit is not.

CH3CH2CH2CH2Br + NaCN

CH3CH2CH2CH2CN + NaBr

benzyltriethylammonium chloride

Mechanism

Cl–

(aqueous)

+N

CH2CH3

CH2CH3

CH2CH3

(aqueous)

CN–+

Cl–+

N

CH2CH3

CH2CH3

CH2CH3

+CN–

(aqueous)

(aqueous)

+N

CH2CH3

CH2CH3

CH2CH3

CN–

(aqueous)

(in butyl bromide)

+N

CH2CH3

CH2CH3

CH2CH3

CN–

Mechanism

(in butyl bromide)

+N

CH2CH3

CH2CH3

CH2CH3

CN–

Mechanism

CH3CH2CH2CH2Br+

+N

CH2CH3

CH2CH3

CH2CH3

Br–

(in butyl bromide)

CH3CH2CH2CH2CN+

21.621.6

Reactions that Lead to Amines:Reactions that Lead to Amines:

A Review and a PreviewA Review and a Preview

Preparation of Amines

Two questions to answer:

1) How is the C—N bond to be formed?

2) How do we obtain the correct oxidation state of nitrogen (and carbon)?

Methods for C—N Bond Formation

Nucleophilic substitution by azide ion (N3–) (Section 8.1, 8.11)

Nitration of arenes (Section 12.3)

Nucleophilic ring opening of epoxides by ammonia (Section 16.12)

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11)

Nucleophilic substitution by ammonia on -halo acids (Section 20.15)

Nucleophilic acyl substitution (Sections 19.4, 19.5, and 19.11)

21.721.7

Preparation of AminesPreparation of Amines

by Alkylation of Ammoniaby Alkylation of Ammonia

Alkylation of Ammonia

Desired reaction is:

2 NH3 + R—X R—NH2 + NH4X

via:

H3N •••• ••R X••

H3N R+ •• ••X

••••

–+ +

then:

H3N •• +

+

H N

H

H

R H3N H+

+ N

H

H

R••

Alkylation of Ammonia

But the method doesn't work well in practice.Usually gives a mixture of primary, secondary,and tertiary amines, plus the quaternary salt.

NH3

RXRNH2

RXR2NH

RX

R3NRX

R4N+

X–

Example

CH3(CH2)6CH2BrNH3 CH3(CH2)6CH2NH2

(45%)

+

CH3(CH2)6CH2NHCH2(CH2)6CH3

(43%)

As octylamine is formed, it competes with ammonia for the remaining 1-bromooctane. Reaction of octylamine with 1-bromooctane gives N,N-dioctylamine.

21.821.8

The Gabriel Synthesis of The Gabriel Synthesis of

Primary AlkylaminesPrimary Alkylamines

Gives primary amines without formation ofsecondary, etc. amines as byproducts.

Uses an SN2 reaction on an alkyl halide to form

the C—N bond.

The nitrogen-containing nucleophileis N-potassiophthalimide.

Gabriel Synthesis

Gives primary amines without formation ofsecondary, etc. amines as byproducts.

Uses an SN2 reaction on an alkyl halide to form

the C—N bond.

The nitrogen-containing nucleophileis N-potassiophthalimide.

Gabriel Synthesis

O

O

N•• •• K+–

The pKa of phthalimide is 8.3.

N-potassiophthalimide is easily prepared bythe reaction of phthalimide with KOH.

N-Potassiophthalimide O

O

N•• ••–

K+

O

O

NH••

KOH

••–

N-Potassiophthalimide as a Nucleophile O

O

N•••• ••R X••

+

O

O

N R••

+ •• ••X••

••–

SN2

Cleavage of Alkylated Phthalimide

O

O

N R•• + H2O

H2N R+

CO2H

CO2H

acid or baseImide hydrolysis is nucleophilic acyl substitution.

Cleavage of Alkylated Phthalimide

Hydrazinolysis is an alternative method of releasing the amine from its phthalimide derivative.

O

O

N R••

H2N R+

O

O

NH

NH

H2NNH2

Example

–

O

O

K+

N + C6H5CH2Cl

DMF

O

O

N CH2C6H5

•• (74%)

•• ••

Example

+ C6H5CH2NH2

O

O

N CH2C6H5

••

H2NNH2

(97%)

O

O

NH

NH

21.921.9

Preparation of Amines by Preparation of Amines by

ReductionReduction

Almost any nitrogen-containing compound canbe reduced to an amine, including:

azidesnitrilesnitro-substituted benzene derivativesamides

Preparation of Amines by Reduction

SN2 reaction, followed by reduction, gives a

primary alkylamine.

Synthesis of Amines via Azides CH2CH2Br

CH2CH2N3

NaN3

(74%) CH2CH2NH2

(89%)

1. LiAlH4

2. H2O

Azides may also bereduced by catalytichydrogenation.


primary alkylamine.

Synthesis of Amines via Nitriles

CH3CH2CH2CH2BrNaCN

(69%)

CH3CH2CH2CH2CN

CH3CH2CH2CH2CH2NH2

(56%)

H2 (100 atm), Ni

Nitriles may also bereduced by lithiumaluminum hydride.


primary alkylamine.

Synthesis of Amines via Nitriles

CH3CH2CH2CH2BrNaCN

(69%)

CH3CH2CH2CH2CN

CH3CH2CH2CH2CH2NH2

(56%)

H2 (100 atm), Ni

The reduction alsoworks with cyanohydrins.

Synthesis of Amines via Nitroarenes

HNO3

(88-95%)

Cl

Cl NO2

H2SO4

(95%)

1. Fe, HCl2. NaOH

Cl NH2

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

Synthesis of Amines via Amides

(86-89%)

COH

O1. SOCl2

2. (CH3)2NH

CN(CH3)2

O

(88%)

1. LiAlH4

2. H2O CH2N(CH3)2

Only LiAlH4 is an

appropriate reducingagent for this reaction.

21.1021.10

Reductive AminationReductive Amination

The aldehyde or ketone equilibrates with theimine faster than hydrogenation occurs.

Synthesis of Amines via Reductive Amination

OC

R

R'

+ NH3

fast

NHC

R

R'

+ H2O

In reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.

Synthesis of Amines via Reductive Amination

OC

R

R'

+ NH3

fast

NHC

R

R'

+ H2O

H2, NiNH2

R

R' C

H

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

Example: Ammonia Gives a Primary Amine O + NH3

H

NH2

H2, Ni

ethanol

(80%)

via:

NH

Example: Primary Amines Give Secondary Amines

H2, Ni ethanol

(65%)

CH3(CH2)5CH2NH

+ H2N

CH3(CH2)5CH

O

via: N

CH3(CH2)5CH

Example: Secondary Amines Give Tertiary Amines

H2, Ni, ethanol

(93%)

+CH3CH2CH2CH

O

N

H N

CH2CH2CH2CH3

Example: Secondary Amines Give Tertiary Amines

CHCH2CH2CH3

N+

Possible intermediates include: N

CH CHCH2CH3

CHCH2CH2CH3

N

HO

21.1121.11

Reactions of Amines:Reactions of Amines:

A Review and a PreviewA Review and a Preview

Reactions of Amines

Reactions of amines almost always involve thenitrogen lone pair.

••N H X

as a base:

••N

C Oas a nucleophile:

Reactions of Amines

basicity (Section 21.4)

reaction with aldehydes and ketones (Sections17.10, 17.11)

reaction with acyl chlorides (Section 19.4),anhydrides (Section 19.5), and esters (Section 19.11)

Reactions already discussed

21.1221.12

Reactions of Amines with Alkyl Reactions of Amines with Alkyl

HalidesHalides

Reaction with Alkyl Halides

Amines act as nucleophiles toward alkyl halides.

•• X+ ••••

••

••N R

H

+ X ••••

••N R

H

+ –

+N R••

H+

Example: excess amine NH2 + ClCH2

NHCH2

(85-87%)

NaHCO3 90°C

(4 mol) (1 mol)

Example: excess alkyl halide

+ 3CH3I

(99%)

methanol heat

CH2N(CH3)3

CH2NH2

+

I–

21.1321.13

The Hofmann EliminationThe Hofmann Elimination

The Hofmann Elimination

A quaternary ammonium hydroxide is the reactantand an alkene is the product.

It is an anti elimination.

The leaving group is a trialkylamine.

The regioselectivity is opposite to the Zaitsev rule.

Quaternary Ammonium Hydroxides

Ag2O H2O, CH3OH

CH2N(CH3)3

+

HO–

are prepared by treating quaternary ammmoniumhalides with moist silver oxide

CH2N(CH3)3

I–

The Hofmann Elimination

160°C

CH2N(CH3)3

+

HO–

on being heated, quaternary ammonium hydroxides undergo elimination

CH2

(69%)

+ N(CH3)3 + H2O

MechanismMechanism H

CH2

+N(CH3)3

–O•••• H••

O••

H••

H

N(CH3)3••

CH2

Regioselectivity

heat

Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule.

N(CH3)3+

HO–

CH3CHCH2CH3H2C CHCH2CH3

CH3CH CHCH3

+

(95%)

(5%)

Regioselectivity

Steric factors seem to control the regioselectivity.The transition state that leads to 1-butene isless crowded than the one leading to cisor trans-2-butene.

Regioselectivity

+N(CH3)3

H

H

H H

CH3CH2

largest group is between two H atoms

C

HC

HH

CH3CH2

major product

Regioselectivity

+N(CH3)3

H

H

H

CH3

largest group is between anH atom and a methyl group

C

HC

CH3 H

CH3

minor product

CH3

21.1421.14

Electrophilic Aromatic Electrophilic Aromatic

SubstitutionSubstitution

in Arylaminesin Arylamines

Nitration of Aniline

NH2 is a very strongly activating group.

NH2 not only activates the ring toward

electrophilic aromatic substitution, it also makes it more easily oxidized.

Attemped nitration of aniline fails because nitric acid oxidizes aniline to a black tar.


Strategy: decrease the reactivity of aniline by converting the NH2 group to an amide

CH(CH3)2

NH2 CH(CH3)2

NHCCH3

O

O

CH3COCCH3

O

(98%)

(acetyl chloride may be used instead of acetic anhydride)


Strategy: nitrate the amide formed in the first step

CH(CH3)2

NHCCH3

O

HNO3

CH(CH3)2

NHCCH3

O NO2

(94%)


Strategy: remove the acyl group from the amide by hydrolysis

CH(CH3)2

NHCCH3

O NO2

KOH

ethanol,heat

CH(CH3)2

NH2 NO2

(100%)

occurs readily without necessity of protecting amino group, but difficult to limit it to monohalogenation

Halogenation of Arylamines CO2H

NH2

Br2

acetic acid

(82%)

CO2H

NH2

Br Br

Monohalogenation of Arylamines

Cl

NHCCH3

O CH3

(74%)

Cl2

acetic acid

NHCCH3

O

CH3

Decreasing the reactivity of the arylamine by converting the NH2 group to an amide allows halogenation to be limited to monosubstitution.

Friedel-Crafts Reactions

The amino group of an arylamine must be protected as an amide when carrying out a Friedel-Crafts reaction. NHCCH3

O

CH2CH3 CH3CCl

O

AlCl3

(57%)

NHCCH3

O CH2CH3

CCH3O

21.1521.15

Nitrosation of AlkylaminesNitrosation of Alkylamines

Nitrite Ion, Nitrous Acid, and Nitrosyl Cation

H+

–O••••

••N O

•• ••••

O•• ••

N O•• ••

••H

H+

O••N O

•• ••

H

H

+••+

••N O

•• ••+O ••

H

H

••

Nitrosyl Cation and Nitrosation

+

••N O

•• ••

Nitrosyl Cation and Nitrosation

+

••N O

•• ••+••N

N••N O

•• ••+

Nitrosation of Secondary Alkylamines

+

••N O

•• ••••N

H

+

N••N O

•• ••+

H+

H

+

N••N O

•• •••• Nitrosation of secondary amines gives an N-nitroso amine.

Example

(CH3)2NH•• NaNO2, HCl

H2O(88-90%)

••(CH3)2N

••N O

•• ••

Some N-Nitroso Amines

N-nitrosopyrrolidine(nitrite-cured bacon)

N

NO

N-nitrosonornicotine(tobacco smoke)

N

NON

(CH3)2N N ON-nitrosodimethylamine

(leather tanning)

Nitrosation of Primary Alkylamines

+ Analogous to nitrosation of secondary amines to this point.

+

••N O

•• ••••N

H

HR

N••N O

•• ••+

H

HR

+H

+

N••N O

•• ••••

R

H


N••N O

•• ••••

R

H

H+

N••N O

••••

R

H H

+

This species reacts further.

••N

••N O

••••

R

HH

+

+

HH

+••N

••N O••

R

H


+

H

••N••N O••

R

H

+N N ••R

H

••O

H

••+

Nitrosation of a primary alkylamine gives an alkyl diazonium ion.

Process is called diazotization.

Alkyl Diazonium Ions

+N N ••R

Alkyl diazonium ions readily lose N2 to give carbocations.

R+ + N N ••••

Example: Nitrosation of 1,1-Dimethylpropylamine NH2

N N+

HONO

H2O

OH

(80%) +

(2%)(3%)

+

– N2

Mechanism 21.2

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

Nitrosation of Tertiary Alkylamines

••NR

R

R

N••N O

•• ••+R

R

R

21.1621.16

Nitrosation of ArylaminesNitrosation of Arylamines

Reaction that occurs is electrophilic aromatic substitution.

Nitrosation of Tertiary Arylamines N(CH2CH3)2

(95%)

1. NaNO2, HCl, H2O, 8°C

2. HO–

N(CH2CH3)2

NO

Similar to secondary alkylamines;

Gives N-nitroso amines

Nitrosation of N-Alkylarylamines

NaNO2, HCl,H2O, 10°C

NHCH3

(87-93%)

NCH3

N O

Nitrosation of Primary Arylamines

Gives aryl diazonium ions.

Aryl diazonium ions are much more stable thanalkyl diazonium ions.

Most aryl diazonium ions are stable under the conditions of their formation (0-10°C).

ArN N+

RN N+ fast

slow

R+ + N2

Ar+ + N2

Example: (CH3)2CH NH2

NaNO2, H2SO4

H2O, 0-5°C (CH3)2CH N N

+HSO4

–

Synthetic Origin of Aryl Diazonium Salts

Ar H

Ar NO2

Ar NH2

Ar N N+

21.1721.17

Synthetic TransformationsSynthetic Transformations

of Aryl Diazonium Saltsof Aryl Diazonium Salts

Transformations of Aryl Diazonium Salts

Ar N N+

Ar H

Ar OH

Ar I

Ar F

Ar BrAr Cl

Ar CN

Preparation of Phenols

Ar N N+

Ar OH

H2O, heat

Example

2. H2O, heat

(CH3)2CH NH2

1. NaNO2, H2SO4

H2O, 0-5°C (CH3)2CH OH

(73%)