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Transcript of Aminas
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
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 H
N
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
NH2H2 N
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, -NH 2 is one of the lowest in order of precedence.
COOHH2 NOH
NH2
H2 NOH
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.
CH3 NH2 N
H
Et3 NNH2
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.
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)
CH3 CH3 CH3 NH2 CH3 OH
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
+ H2 O CH3 NH2 H3 O+++
[ CH3NH2 ] [H3 O+
]
[CH3 NH3+
]2.29 x 10-11==Ka pKa = 10.64
H
H
CH3 - N H- O-H
H
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 CH3 COOH CH3NH3+
CH3COO-
Keq = 7.6 x 105
+ +
pKa 10.64pKa 4.76(stronger
acid)(weaker
acid)
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
CH3 NH2
NH3
CH3 CH2 NH2C6 H1 1 NH2
( CH3 ) 2 NH( CH3 CH2 ) 2 NH
( CH3 ) 3 N( 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 H2 O
H2 ONH2
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
O2 N
NH2O2 N
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
NH2H2 N H2 N C NH2
NH2
C
NH2
NH2H2 N
Three equivalent contributing structures
+ +
+
:
:
: :
:
++
Guanidine Guanidinium ion
C
NH
NH2H2 N H2 N C NH2
NH2+
H2 O 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
HClH2 O
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 LiAlH 4
• reduction of nitriles to a 1° amine• nitration of arenes followed by reduction of the
NO 2 group to a 1° amine
23-23-3030
PreparationPreparation
� Alkylation of ammonia and amines by S N2 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
CH3 Br NH3 CH3 NH3+ 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 CH2 ClK
+ N3
-
Ph CH2 N31. LiAlH4
2. H2OPh CH2 NH2
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)
ArCO3 H 1 . K+
N3-
2 . H2 O
1 . LiAlH4
2 . H2 ON3
OH
NH2
OH
O
Note retention of configuration, trans trans
23-23-3333
Reaction with HNOReaction with HNO 22
� Nitrous acid, a weak acid, is most commonly prepared by treating NaNO 2 with aqueous H 2SO 4 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 HNO 22
� NO + is formed in the following way.• Step 1: Protonation of HONO.• Step 2: Loss of H 2O.
• We study the reactions of HNO 2 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 HNO 22
• 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.
Me2 N1. NaNO2 , HCl, 0-5°C
2. NaOH, H2ON=OMe2 N
N,N-Dimethyl-4-nitrosoanilineN,N-Dimethylaniline
23-23-3636
Secondary Amines with HNOSecondary Amines with HNO 22
• 2° Aliphatic and aromatic amines react with NO + to give N-nitrosamines.
N-H HNO2 N-N=O H2 O
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
RNHRNH 22 with HNO with HNO 22
� 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 N 2 to give a carbocation.
� Diazonium ion:Diazonium ion: An RN 2+ or ArN 2
+ ion
23-23-3838
1° RNH1° RNH 22 with HNO with HNO 22
� 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+
- H2 O
R+
•• ••
••
•• •• ••
23-23-3939
1° RNH1° RNH 22 with HNO with HNO 22 (Aliphatic) (Aliphatic)
� Aliphatic diazonium ions are unstable and lose N 2 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° RNH 22 with HNO with HNO 22
� Tiffeneau-Demjanov reaction:Tiffeneau-Demjanov reaction: Treatment of a β-aminoalcohol with HNO 2 gives a ketone and N 2..
CH2 NH2
OH
HNO2
O
H2 O N2
β+ + +
A β-aminoalcohol Cycloheptanone
α
23-23-4141
Mechanism of Tiffeneau-DemjanovMechanism of Tiffeneau-Demjanov
• Reaction with NO + gives a diazonium ion.• Concerted loss of N 2 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 stabilization of a carbocation by an adjacent lone pair.adjacent 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 HNO 2 2 (Aromatic)(Aromatic)
� The -N 2+ group of an arenediazonium salt can
be replaced in a regioselective manner by these groups.
Ar-NH2
HNO2Ar-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-OH
Schiemannreaction
Sandmeyerreaction0-5°C
23-23-4545
1° ArNH1° ArNH 22 with HNO with HNO 22
� 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° ArNH 22 with HNO with HNO 22
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° ArNH 22 with HNO with HNO 22
� Problem: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)
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 OAg2 O
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 ) 3 N 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 β-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 -NR 3
+ group.• Hydroxide ion preferentially approaches and
removes the least hindered hydrogen and, thus, gives the least substituted alkene.
• Bulky bases such as (CH 3) 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 β-hydrogen, it undergoes thermal decomposition to give an alkene.
CH2 N-CH3
CH3
H2 O2
O
CH3
CH2 N-CH3 H2 O++
+
-
An amine oxide
O
CH3
CH2 N-CH3
H 100-150°CCH2 (CH3 ) 2 NOH+
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
: