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Chapter 23

Amines

23-1

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
CH 3 - N H 2 Methylamine (a 1 amine) CH 3 - N H C H3 Dimethylamine (a 2 amine) CH 3 CH 3 - N : CH 3 Trimethylamine (a 3 amine) : :

23-2

Structure & Classification


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
CH 3 N- H : CH 3 CH 2 - N - C H 3

Aniline N-Methylaniline Benzyldimethylamine (a 1 aromatic amine) (a 2 aromatic amine) (a 3 aliphatic amine)

:
NH2

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Structure & Classification


heterocyclic amine: an amine in which nitrogen is one of the atoms of a ring

H H Pyrrolidine Piperid ine (h eterocyclic alip hatic amines)

H Pyrrole Pyridine (h eterocyclic aromatic amin es)

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Structure & Classification


Example: classify each amino group by type
CH3 H (a) N H (S)-Con iine (b) H N CH3 (c) O Cocain e O C6 H5 N COOCH3

N (S)-N icotine

Caffein

Morphine

Heroin

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Structure & Classification


Aliphatic

amines: replace the suffix -e of the parent alkane by -amine


NH2 NH2 2-Propanamine (S)-1-Phen ylethanamine H2 N NH2

1,6-Hexanediamine

23-6

Nomenclature
The

IUPAC system retains the name aniline


NH2 NH2 NH2 NH2

OCH 3 N O2 CH3 Aniline 4-Nitroaniline 4-Methylaniline 3-Methoxyaniline (p-Nitroaniline) (p-Toluidine) (m-Anisidine)

23-7

Nomenclature
Among

the various functional groups discussed in the text, -NH2 is one of the lowest in order of precedence
H2 N OH OH NH2 (S)-2-Amino-3-methyl1-butanol H2 N COOH

2-Aminoethanol

4-Aminobenzoic acid

23-8

Nomenclature
Common

names for most aliphatic amines are derived by listing the alkyl groups bonded to nitrogen in one word ending with the suffix amine
H CH3 NH2 NH2 N Et 3 N

Meth ylamine tert - Butylamine D icyclopen tylamine Triethylamin e

23-9

Nomenclature
When

four groups are bonded to nitrogen, the compound is named as a salt of the corresponding amine
Me4 N Cl
+ -

+ NCH2 ( CH2 ) 1 2 CH3

Cl

Ph CH2 NMe3 OH Benzyltrimeth ylammonium hydroxid e

Tetramethy Tetrad ecylpyrid inium ch loride ammonium (Cetylp yridin ium chloride) 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 of groups 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
the u nsh ared electron pair in the fourth sp 3 hybrid orbital H H Et Et Me Me (S)-Ethylmethylamin e (R )-Ethylmethylamin e N N

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Chirality of Amines
in practice, however, they cannot be resolved because they undergo pyramidal inversion, which converts one enantiomer to the other
Un hy bri di z e d 2p orbi tal sp 3 N H Me N sp 2 Et N sp 3 The trans i ti on state has a p l ane o f s ym m e try ; i t i s ac hi ral

H Et Me S Enan ti om e r

R Enan ti om e r

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Chirality of Amines
pyramidal inversion is not possible with quaternary ammonium ions, and their salts can be resolved

Cl

ClEt Me R Enan tiomer N

N Et Me S Enan tiomer

23-13

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) is less than that between O and H (3.5 - 2.1 = 1.4)
CH3 CH3 MW (g/mol) bp (C) 30.1 -88.6 CH3 NH2 31.1 -6.3 CH3 OH 32.0 65.0

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Basicity
All

amines are weak bases, and aqueous solutions of amines are basic
H CH3 -N + H-O-H H Methylamine H + - O-H CH3 -N-H H Methylammoniu m h yd roxide

it is common to discuss their basicity by reference to the acid ionization constant of the conjugate acid
CH3 NH3 Ka =
+

+ H2 O
+ +

CH3 NH2 + H3 O+ = 2.29 x 10


-1 1

[ CH3 NH2 ] [H3 O ] [CH3 NH3 ]

pK a = 10.64
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Basicity
using values of pKa, we can compare the acidities of amine conjugate acids with other acids
CH3 NH2 + CH3 COOH pK a 4.76 (s tronger acid) CH3 NH3 + CH3 COO pK a 10.64 (w eak er acid )
+ -

pK eq = -5.88 Ke q = 7.6 x 10
5

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Basicity-Aliphatic Amines
Aliphatic

Amines
Structure NH3 CH3 NH2 CH3 CH2 NH2 C6 H1 1 NH2 p Ka 9.26 10.64 10.81 10.66 pK b 4.74 3.36 3.34 3.19

Amine Ammon ia Primary Amines methylamin e ethylamine cyclohexylamine Secon dary A min es dimethylamine dieth ylamine Tertiary Amines trimeth ylamine triethylamin e

(CH3 ) 2 NH 10.73 (CH3 CH2 ) 2 NH 10.98 (CH3 ) 3 N (CH3 CH2 ) 3 N 9.81 10.75

3.27 3.02 4.19 3.25

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Basicity-Aromatic Amines
Amine Aromatic A min es An iline 4-Methylanilin e 4-Ch loroaniline 4-N itroanilin e CH3 Cl O2 N NH2 NH2 NH2 NH2 4.63 5.08 4.15 1.0 Structure pK a of Conju gate A cid

Heterocyclic Aromatic A min es Pyrid ine Imidazole N H N N 6.95 5.25

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Basicity-Aromatic Amines
aromatic amines are considerably weaker bases than aliphatic amines
NH2 + H2 O Cycloh exylamine NH3 OH Cyclohexylammonium hydroxid e NH3 + OHA niliniu m h yd roxide pK a = 4.63
+ -

pK a = 10.66

NH2 + H2 O A niline

23-19

Basicity-Aromatic Amines
Aromatic

amines are weaker bases than aliphatic amines because of two factors
resonance stabilization of the free base, which is lost on protonation
H N H H+ H N H + H N H + H N

H
.

. .

H
. ..

un hybridized 2p orb ital of N H H nitrogen is sp 2 h yb rid ized


23-20

H . H

N H

Basicity-Aromatic Amines
the greater electron-withdrawing inductive effect of the sp2-hybridized carbon of an aromatic amine compared with 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

23-21

Basicity-Aromatic Amines
4-nitroaniline is a weaker base than 3-nitroaniline
O2 N NH2 3-N itroanilin e pK a 2.47 O2 N NH2

4-N itroaniline pK a 1.0


de localiz ation of th e n itrog en lon e p air on to th e oxyg en atom s of th e n itro grou p

O +N O NH2

O +N NH2 +

23-22

Basicity-Aromatic Amines
Heterocyclic

aromatic amines are weaker bases than heterocyclic aliphatic amines


N N H Piperidine p Ka 10.75 N Pyridin e pK a 5.25 N H Imid azole pK a 6.95

23-23

Basicity-Aromatic Amines
in pyridine, the unshared pair of electrons on N is not part of the aromatic sextet
.

. .

. .

H H

N H

an sp 2 h yb rid orbital; th e electron p air in this orbital is n ot a p art of the aromatic s extet nitrogen is sp 2 h yb rid ized

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)
23-24

Basicity-Aromatic Amines
Imidazole
This ele ctron pair is not a part of the aromatic s extet Aromaticity is maintained when imidazole is protonate d H
+ H2 O

:
N

This ele ctron pair is a part of the aromatic se xtet

N+

+ OH-

H Imidazole

:
N

H Imidazoliu m ion

:
N

23-25

Basicity-Guanidine
Guanidine

is the strongest base among neutral organic compounds


NH H2 N C NH2 Guan idine
+

NH2 H2 O

+
+

OH Guanid inium ion

H2 N C NH2

p Ka = 13.6

its basicity is due to the delocalization of the positive charge over the three nitrogen atoms
+
H2 N

N H2

N H2

H2 N

N H2

N H2

N H2

H2 N

Thre e e quivale nt contributing structu res

N H2

23-26

Reaction with Acids


All

amines, whether soluble or insoluble in water, react quantitatively with strong acids to form water-soluble salts
OH HO NH2 + HCl H2 O HO HO (R)-N orepinep hrine h yd roch loride (a w ater-s olu ble salt) OH NH3 + Cl-

HO (R)-N orepinep hrine (on ly s ligh tly s olu ble in w ater)

23-27

Preparation
We

have already covered these methods

nucleophilic ring opening of epoxides by ammonia and amines (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)

23-28

Preparation
Alkylation

of ammonia and amines by SN2


SN 2
CH3 NH 3 + Br Methylammonium bromide

CH3 Br + N H3

unfortunately, such alkylations give mixtures of products through a series of proton transfer and nucleophilic substitution reactions
CH3 Br + NH3 CH3 NH3 Br + (CH3 ) 2 NH2 Br
+

+ (CH3 ) 3 NH Br + (CH3 ) 4 N Br

23-29

Preparation via Azides


Alkylation
N3
-

of azide ion
N + N N :RN 3 R N + N

-:

Azide ion (a good nucleophile )

Ph CH2 Cl Benzyl chloride

N:

An alk yl azide
-

K N3

Ph CH2 N3 2. H2 O Benzyl azide

1. LiAlH4

Ph CH2 NH2 Benzylamine

23-30

Preparation via Azides


alkylation of azide ion
ArCO3 H Cyclohexen e O 1,2-Epoxycyclohexane (chiral) OH N3 trans- 2-Azid ocyclohexan ol (racemic) 1 . LiAlH4 2 . H2 O OH NH2 t rans- 2-Aminocyclohexan ol (racemic) 1 . K N3 2 . H2 O
+

23-31

Reaction with HNO2


Nitrous

acid, a weak acid, is most commonly prepared by treating NaNO2 with aqueous H2SO4 or HCl
HNO2 + H2O H3O + NO2
+ -

pK a = 3.37

In

its reactions with amines, nitrous acid

participates in proton-transfer reactions is a source of the nitrosyl cation, NO+, a weak electrophile

23-32

Reaction with HNO2


NO+

is formed in the following way


+

(1)

H O N O + H

+ H O N O H H O + H +

(2)

N O

+ N O

The nitrosyl cation

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

23-33

Amines with HNO2


3 aliphatic amines, whether water-soluble or waterinsoluble, are protonated to form water-soluble salts 3 aromatic amines: NO+ is a weak electrophile and, as such, participates in EAS
Me2 N 1 . NaNO2 , HCl, 0-5C Me2 N N=O

2 . NaOH, H2 O N ,N-Dimethylaniline

N,N-D imethyl-4-nitrosoaniline

2 aliphatic and aromatic amines react with NO+ to give N-nitrosoamines


N-H + HNO2 Piperidin e N-N=O + H2 O N-N itrosopiperidin e

23-34

Amines with HNO2


Reaction

of a 2 amine to give an N-nitrosamine

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

+ N O

(1) H

N H H O H

+ N

(2)

N=O

+ + H O H H

N=O

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RNH2 with HNO2


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: an RN2+ or ArN2+ ion

23-36

1 RNH2 with HNO2


Formation

of a diazonium ion
H : : : keto-enol tautomerism

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


R-NH2 + A 1 aliphatic amine + : N O: : : : : :

Step 2: protonation followed by loss of water


R-N=N-O-H A diazotic acid R H
+

R -N - N = O : A n N-nitrosamine

R-N=N-O-H A diazotic acid

R-N + N

N N

H + O-H

-H2 O R
+

: : : :

A diazoniu m ion

A carbocation

23-37

1 RNH2 with HNO2


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 1 and/or 2
Cl

(5.2%)
OH
N H 2 N a N O2 , H Cl + OH

0-5oC

(13.2%)
+

(25%)

(25.9%)

(10.6%)

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1 RNH2 with HNO2


Tiffeneau-Demjanov

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


OH CH2 NH2 + HNO2 A-aminoalcohol O + H2 O + N2 Cycloheptanone

23-39

1 RNH2 with HNO2


reaction with NO+ gives a diazonium ion concerted loss of N2 and rearrangement followed by proton transfer gives the ketone
:

: OH
CH2NH 2 HNO2

: :O H + CH2 :

: O-H
CH2 N N:

-N2

(A diazonium ion)
:

+ O H
CH2

A resonance-stabilized cation

proton transfer to H 2O

Cycloheptanone

23-40

1 ArNH2 with HNO2


The

-N2+ group of an arenediazonium salt can be replaced in a regioselective manner by these groups
H2 O HBF4 HCl, CuCl HNO2 0-5C
+ (-N ) 2

Ar-OH Ar-F Ar-Cl Ar-Br Ar-CN Ar-I Ar-H San dmeyer reaction Sch ieman n reaction

Ar-NH2

Ar-N2

HBr, CuBr KCN, CuCN KI H3 PO2

23-41

1 ArNH2 with HNO2


A

1 aromatic amine can be converted to a phenol


NH2 Br 1 . HNO2 2 . H2 O, heat CH3 2-Bromo-4methylanilin e CH3 2-Bromo-4meth ylp henol OH Br

23-42

1 ArNH2 with HNO2


Problem: what reagents and experimental conditions will bring about this conversion?
CH3 (1) N O2 CH3 (2) N O2 COOH (3) N H2 COOH
(4)

COOH

OH

23-43

1 ArNH2 with HNO2


Problem:

Show how to bring about each conversion


CH3 Cl

(5) CH3 NH2 (6) (8) CH3 C N (7) CH 3 CH2 NH2

CH3 NH2 (9) Cl

CH3

Cl

Cl

Cl

23-44

Hofmann Elimination
Hofmann

elimination: thermal decomposition of a quaternary ammonium hydroxide to give an alkene


Step 1: formation of a 4 ammonium hydroxide
CH3 I + CH2 - N - CH 3 + Ag2 O

H2 O

CH3 (Cyclohexylmethyl)trimethyl- Silver oxide ammonium iodide CH3 OH+ CH2 - N - CH 3 + AgI

CH3 (Cyclohexylmethyl)trimethylammonium hydroxide

23-45

Hofmann Elimination
Step 2: thermal decomposition of the 4 ammonium hydroxide
CH 3 OH+ CH 2 -N - CH 3 CH 3 (Cyclohexylme thyl)trimethylammonium hydroxide CH2 + Methyle necyclohexane ( CH 3 ) 3 N + H2 O 160

Trime thylamine

23-46

Hofmann Elimination
Hofmann

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


CH3
+

heat
-

N(CH3 ) 3 OH

CH2 + (CH3 ) 3 N + H2 O

Hofmanns

rule: any -elimination that occurs preferentially to give the least substituted alkene as the major product is said to follow Hofmanns rule

23-47

Hofmann Elimination
HO H C H CH3 CH 2 C H H + N ( CH3 ) 3 HOH

E2 reaction (concerted elimination)

H CH3 CH 2

H C C H N ( CH3 ) 3

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
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Cope Elimination
Cope

elimination: thermal decomposition of an amine oxide


Step 1: oxidation of a 3 amine gives an amine oxide
O CH2 N-CH3 + H2 O2 CH3
+

CH2 N-CH3 + H2 O CH3 An amine oxide

Step 2: if the amine oxide has at least one -hydrogen, it undergoes thermal decomposition to give an alkene
H + 100-150C CH2 N-CH3 CH3 O
-

CH2 Meth ylen ecyclohexane

(CH3 ) 2 NOH N,N-D imethylhydroxylamine 23-49

Cope Elimination
Cope elimination shows syn stereoselectivity but little or no regioselectivity mechanism: a cyclic flow of electrons in a sixmembered transition state
C H
-

C N+ :O

C CH3 CH3 heat H

C CH3 CH3

an alken e N,N-d imeth ylhydroxylamin e

:
N O

Transition s tate

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Amines
End Chapter 23
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