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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
Structure & ClassificationStructure & Classification
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
Structure & ClassificationStructure & Classification
• 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
NomenclatureNomenclature
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
NomenclatureNomenclature
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
NomenclatureNomenclature
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
Chirality of AminesChirality of Amines
• In practice, however, they cannot be resolved because they undergo inversion, which converts one enantiomer to the other.
23-23-1313
Chirality of AminesChirality of Amines
• 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
Basicity-Aromatic AminesBasicity-Aromatic Amines
• 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
Basicity-Aromatic AminesBasicity-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.
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
Basicity-Aromatic AminesBasicity-Aromatic Amines
• 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
Basicity-Aromatic AminesBasicity-Aromatic Amines
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
Basicity-Aromatic AminesBasicity-Aromatic Amines
• 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
Basicity-Aromatic AminesBasicity-Aromatic Amines
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 carbo- cation
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
1° ArNH1° ArNH22 with HNO with HNO22
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
1° ArNH1° ArNH22 with HNO with HNO22
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
Hofmann EliminationHofmann Elimination
• 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 EliminationHofmann Elimination
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
Hofmann EliminationHofmann Elimination
• 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
+
-