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Unit 4 Amines
Structure and properties
Nomenclature
Reactions (some review)
Synthesis (some review)
Spectroscopy – mass spec, IR, NMR
Amines-Introduction

Amines and amine derivatives are found throughout
biological systems.
 Amino acids (proteins)
 Bioregulators
 Neurotransmission
 Vitamins
 drugs
Amines-Introduction
Amines-Introduction
O
H 3C
O
CH3
N
N
N
N
CH3
caffeine
Biologically active basic amines obtained
from plants are called alkaloids.
Amines-Introduction
There are many man-made drug that are amines.
H
H
N
N
CH3
CH3
methamphetamine
levomethamphetamine
vasoconstrictor
H
N
OH
H
H
N
pseudoephedrine
amphetamine
Nasal decongestant
CH3
Amine- Structures
Amines are derivatives of ammonia NH3
Amines are classified based on the number of
alkyl groups attached to nitrogen.
R-NH2 primary amine (1°)
R2-NH secondary amine (2°)
R3-N
tertiary amine (3°)
R4-N+, X- quaternary ammonium salt(4°)
Amine- Nomenclature
Common amines are named based on the alkyl
groups attached to the nitrogen.
Alkylamine
dialkylamine
trialkylamine
tetralkylamine
ethylamine
dimethylamine
butyldiethylamine
tetraethylammonium chloride
Amine- Nomenclature
Name and classify the following amines.
(CH3CH2)2NCH3
NH CH3
H
CH2NH2
N
NH2
Amine- Nomenclature
The amine is named as a substituent group
when there is a higher priority group.
OH
NHCH3
NH2CH2CH2CH2CO2H
4-aminobutanoic acid
2-methylaminophenol
NH2
O
N
CH2CH3
4-(ethylmethylamino)cyclohexanone
N(CH3)2
OH
3-aminocyclohexene
CH3
Amine- Nomenclature (IUPAC)
IUPAC names are based on the longest carbon chain.
 Drop the –e of the alkane name and add-amine.
 Substituents on nitrogen have N- prefix.
NH2
NH2
CH3CH2CHCH3
CH3CHCHCH3
CH3
N(CH3)2
CH3CH2CHCHCHCH3
CH3 CH3
NHCH3
CH3CH2CHCH3
Aromatic Amines
When the amino group is bonded to an aromatic
ring the parent compound is called an aniline.
NH2
NH2
N(CH3)2
CH3
aniline
N,N-dimethylaniline
4-methylaniline
or
P-toluidine
Heterocyclic Amines
H
N H
N H
N
N
pyrrole
pyrrolidine
pyridine
aziridine
H
N
N
N
N
H
H
piperidine
piperazine
N
pyrimidine
N
N
N
N
purine
H
Structure of Amines
Nitrogen atoms with 3 or 4 single bonds are sp3 hybridized.
H
H
N
H
H
N
CH3
CH3
H-N-H bond angle is about 107°
The steric interactions of larger substituents
increases the bond angle C-N-C is about 108 °
Structure of Amines
The nitrogen atom is potentially a stereocenter. However nitrogen
inversion occurs rapidly at room temperature.
Chiral Amines:
Amines with a chiral carbon.
Quaternary ammonium cpds with four different groups bonded to
nitrogen.
Amines that are unable to achieve the planar transition state (ie small
rings). pp. 875
Structure of Amines
Quaternary ammonium salt with four different groups bonded to nitrogen.
The counter ion can be Cl-, Br-, OH- etc.
(R)
+
N
(CH3)2CH
CH2CH3
H3C
(S)
N
CH3CH2
+
CH(CH3)2
CH3
Physical properties of Amines
Amines (1 °,2 ° and 3 °) are highly polar materials because of the lone
pair of electrons on nitrogen.
 The N-H bond is less polar than the O-H bond.
 Weaker hydrogen bonding.
 Tertiary amines cannot hydrogen bond but are hydrogen bond
acceptors.
Physical properties of Amines
The strength and number of hydrogen bonds found in an amine
influence melting points, boiling points, and water solubility.
Compound
bp
(C)
Type
MW
(CH3)3N:
3
3 amine
59
CH3OCH2CH3
8
ether
60
CH3NHCH2CH3
37
2 amine
59
CH3CH2CH2NH2
48
1 amine
59
CH3CH2CHO
49
aldehyde
58
CH3COCH3
56
ketone
58
CH3CH2CH2OH
97
alcohol
60
Physical properties of Amines
Methylamine
ethylamine
n-propylamine
type
1°
1°
1°
MW
31
45
59
mp
-93
-81
-83
bp
-7
17
48
dimethylamine
diethylamine
2°
2°
45
73
-96
-42
7
56
trimethylamine
triethylamine
3°
3°
59
101
-117
-115
3.5
90
Physical properties of Amines





Amines up to about 6 carbons are water soluble.
Amines accept hydrogen bonds from water and alcohols.
Branching increases solubility.
Amines have very strong odors (rotting fish).
 1,5-pentanediamine (cadaverine).
 1,4-butanediamine (putrescine).
Pure amine are clear (liq. or solids) but oxidation from
atmospheric oxygen often results in the materials being
dark colored.
Physical properties of Amines
Amines are bases, in the presence of acids the lone pair of electrons
act as a proton acceptor (Bronsted-Lowry bases).
R NH2
+
HCl
R NH3
+
Cl-
The lone pair of electrons on nitrogen can also act as a nucleophile
(Lewis base).
H
H
R NH2
+
H
H
C Cl
H
+
R N
H
H
H
Cl-
Physical properties of Amines
H
R N
Kb
+
H O
H
R N H
H
H
H
ammonium ion
[RNH3+] [OH - ]
______________
Kb =
[RNH2 ]
Amines are weak bases:
Kb = 10-3 - 10-10 Larger Kb is stronger base.
pKb = 3 - 10
Smaller pKb is stronger base.
+
OH
-
hydroxide ion
Physical properties of Amines
type
ammonia
methylamine
ethylamine
n-propylamine
1°
1°
1°
pKb
4.74
3.36
3.36
3.32
dimethylamine
diethylamine
2°
2°
3.28
3.01
trimethylamine
triethylamine
3°
3°
4.26
3.24
aniline
pyridine
1°
heterocyclic
9.4
8.75
see page 878
Physical properties of Amines




Amines are converted to the water soluble ammonium salt
by treatment with an acid. Examples: HCl, HBr, H2SO4 and
organic acids.
The salt can be converted back to the free amine by
treatment with a strong base. Examples: NaOH, KOH,
Na2CO3 and bicarbonate.
Amines are often isolated and purified using acid/base
extraction. page 881
Amine salts are more stable to air oxidation than the free
amine and have little or no odor.
Physical properties of Amines
Spectroscopy of Amines
Spectroscopy of Amines
propylamine

Spectroscopy of Amines
piperidine

Spectroscopy of Amines

Benzylamine
Spectroscopy of Amines

N-methylaniline
Spectroscopy of Amines
Reactions of Amines (review)
Primary amines react with ketones and aldehydes to give imines.
Analogous products are obtained for hydroxylamine, hydrazine,
semicarbazide and carbazide. Write the mechanism for this
reaction. (Note: The acid conditions.)
Formation of Imines


The formation of an imine involves an initial nucleophilic attack by ammonia or a primary amine on the
carbonyl carbon. Followed by subsequent loss of a water molecule.
The C=O becomes a C=N-R group where R= H, alkyl or aryl
H+
H3C
H3C
H2N
H
H CH3
R
R N C OH
C O
C O
Ph
Ph
CH3
R N C OH
H
Ph
CH3
H2O
H
CH3
H+
R N C O
H
Ph
H
H
R N C OH
Ph
H
+ H3O+
Ph
CH3
CH3
R N C
R N C
H
H
Ph
CH3
R N C
Ph
H2O
Ph
Reactions of Amines (review)
The aromatic ring of aniline derivatives are highly activated for
electrophilic aromatic substitution reactions. As shown above the
sigma complex is stabilized at the ortho and para positions by the
non-bonding electron on the nitrogen. Is the ring activated in the
presents of an acid?
Reactions of Amines (review)
NH2
NH2
NO2
xs Cl2
Cl
NO2
+
2 HCl
NaHCO3
Cl
What function does the sodium bicarbonate serve in the above
reaction?
Give two reasons why anilines can not be nitrated directly using
HNO3/H2SO4?
Reactions of Pyridine
The pyridine ring is deactivated towards electrophilic aromatic
substitution because of the electronegative nitrogen in the ring.
Additionally the non-bonding electron on the nitrogen would react
with the electrophile. Reaction only occurs under extreme
conditions. Note: That substitution is in the 3-position.
Reactions of Pyridine
The pyridine ring is activated towards nucleophilic aromatic
substitution. With substitution occurring at either the 2- or 4position. The sigma complex is stabilized by the negative charge
being on nitrogen.
Alkylation of Amines
Amines are good nucleophiles that react with alkyl
halides via a Sn2 mechanism.
Reaction with primary halides give alkylated ammonium halides.
Secondary halides are less reactive than primary halides and
often give poor yields or elimination products.
Tertiary halides do not react because of steric hindrance.
Note: The that °3 halides can still under go elimination.
Alkylation of Amines
The above reaction gives an incomplete picture of the chemistry
involved in the alkylation of an amine with an alkyl halide.
Alkylation of Amines
The reaction of one mole of primary amine with one mole of alkyl
halide will give a mixture of starting primary amine, secondary
amine, tertiary amine and quaternary ammonium salts.
There two methods that can be used to avoid obtaining mixtures
of products when alkylating amines with alkyl halides.
Alkylation of Amines
Exhaustive alkylation (methylation) involves reacting the amine with
an excess of alkyl halide in the presence of an acid scavenger.
R NH2
+
3 CH3 Cl
NaHCO3
R N
(CH3)3 Cl -
(> 90%)
Alkylation of Amines
The use of a large excess of ammonia results in monoalkylation.
The excess ammonia is simply allowed to boil of at the end of the
reaction. This synthetic approach is useful in many situations but
is often limited by the cost of the alkyl halide.
NH3
10 moles
+
R'
CH2 X
1 mole
R'
+
CH2 N H3
X-
Acylation of Amines
Amides are produced by the treatment of primary and secondary
amines with acid halides in the presents of a non-nucleophilic acid
scavenger.
The reaction involves the nucleophilic attack of the amine on the
carbonyl carbon (the electrophilic center) of the acid halide
followed by loss HX.
Amides are far less basic and nucleophilic than amines. As a
result mono-acylation product is normally produced.
Why is the amide less basic and nucleophilic than the amine?
Acylation of Amines
O-
O
R'
C Cl
+
R'
R NH2
Cl
NH2
R
O
O
R'
R'
Cl
C NHR
+
Cl
-
H
NH2
R
O
R'
C NHR
+
Cl -
O
Base
R'
C NHR
+
H Base
+
H
The base is typically pyridine, a tertiary amine or bicarbonate.
The yields are generally very good ( > 90 %).
Cl -
Acylation of Amines
The acyl group in an amide can be easily removed by hydrolysis
with aqueous acid. As a result acylation can be used as a means
of temporary protecting the amine group as the amide while
conducting other reactions that would produce undesired change
in the amine. The acyl group acts as a Masking agent.
Many reactions can not be done directly on the aromatic ring of
aniline either because the amine will react with the reagents or
multiple substitution occur.
Acylation of Amines
H
O
NH2
Cl
+
N
AlCl3
+
aluminum complexs
O
The Friedel-Crafts acylation of the ring fails in the above
reaction. However, if the amine of the aniline is acylation first
then the ring can be acylated.
O
O
O
NH2
O
+
CH3CCl
Base
NHCCH3
Cl
NHCCH3
AlCl3
O
Acylation of Amines
O
NHCCH3
NH2
H+ / heat
pH adjust
O
O
Why do we need to do a final pH adjustment?
Sulfonylation of Amines
The reaction of amines with sulfonyl chlorides is analogous
to that of acyl halides.
O
R'
S
O
O
NaOH
Cl
+
R NH2
R'
S
NHR
O
The sulfa drugs are antibacterial agents that contain the
sulfonamide group.
Elimination Reactions involving Amines
Amines can under go two different types of elimination
reactions that give alkenes.
Hofmann elimination: An amine is exhaustively methylated to
the quaternary ammonium salt. The halide salt is converted to
the hydroxide salt by treatment with silver oxide. The
quaternary ammonium hydroxide is then thermally decomposed
via a conserted E2 mechanism to give the alkene.
Cope Elimination: A tertiary amine is converted to the amine
oxide by treatment with hydrogen peroxide or a peroxyacid.
The amine oxide is then thermally decomposed to give an
alkene.
Both reactions generally give the least-substituted alkene.
Elimination Reactions involving Amines
Hofmann elimination:
acid scavenger
R NH2
+
R N(CH3)3 I
3 CH3 I
-
+
2 HI
trimethyl amine
a good leaving group
R N(CH3)3 I
CH3CH2CH N(CH3)3 OH
+
-
1/2 Ag2O
R N(CH3)3 OH
heat
CH3CH2CH CH2
+
H2O
+
N(CH3)3
CH3
For R = 2-butyl the product is 95 % 1-butene, the least substituted
alkene. Onle 5% of the product is the Saytzeff product.
Hofmann elimination:
Requirements an anti coplanar stereochemistry.
Hofmann elimination:
Predict the products of the following reactions.
CH3
1) CH3I
N
CH3
2) Ag2O
3) heat
CH3
NH2
1) CH3I
2) Ag2O
3) heat
1) CH3I
NHCH2CH3
2) Ag2O
3) heat
Cope elimination:
The oxidation of amines can lead to a number of different
products depending on the type of starting amine.
Oxidation of °1 amines results in the formation of hydroxyl
amines which are oxidized to nitroso cpds which are then
oxidized to nitro cpds.
°2 amines are oxidized to hydroxyl amines.
°3 amines are oxidized to amine oxides. The Cope elimination
involves the thermal decomposition of these amine oxides.
Cope elimination:
The oxidation of the °3 amine is easily done using either 30% or
50% hydrogen peroxide. The reaction is very exothermic and
the addition of the peroxide must be carefully regulated to
avoid over heating the reaction.
R
R N
R
°3 amine
R
+
H2O2
R N O
R
°3 amine oxide
+
H2O
Cope elimination:
Heating the amine oxide results in the elimination of a dialkyl
hydroxylamine. The reaction occurs via a concerted E2
mechanism that requires syn stereochemistry to occur. The
reaction occurs under milder conditions than the Hofmann
elimination.
CH3
CH3CH2CH N O
CH3 CH3
heat
CH3CH2CH CH2
+
HO N(CH3)2
Cope elimination:
Predict the products of the following reactions.
1) H2O2
N
2) heat
1) H2O2
N
2) heat
(CH3)2N
1) H2O2
2) heat
Reactions with Nitrous Acid
Treatment of primary aromatic amines with sodium nitrite
under acidic conditions arenediazonium salt. This process is
called diazotization of an amine. Once the diazonium salt is
made the diazonium group can be replace by many different
groups.
NH2
NaNO2
HCl
What about diazonium salts made from alkylamines?

N2 Cl -
Reactions with Nitrous Acid
Reactions with Nitrous Acid
H3O +
R N N OH
H
R N N O H
R N N
diazonium ion
+
H2O
Reactions with Nitrous Acid
Reactions of diazonium salts.
Synthesis via diazonium salts
Devise a synthetic pathway for the following reactions.
NO2
CN
O
O
H2N
HO
N2 Cl -
O2N
NO2
N N
OH
Synthesis of Amines via reduction
Reductive amination is a two step process that adds an alkyl
group to ammonia, a primary or secondary amine.
1. The first step is the formation of the imine or oxime
derivative of an aldehyde or ketone.
2. The imine/oxime is then reduced to give the amine.
The reaction is done on an industrial scale using H2
over a Ni catalyst. Laboratory scale process
generally rely on hydride reducing agents such as
LAH.
Synthesis of Amines via reduction
Primary amines via reductive amination:
O
R
N
H2NOH
R'
H+
R
OH
NH2
reduction
R'
R
R'
R=R'= alkyl, aryl and hydrogen
R=R'
The hydrogenation can be done with 15-60 psig of H2 at 140-60°C over 0.2%
supported Ni catalyst.
Synthesis of Amines via reduction
Secondary amines via reductive amination:
a primary amine
O
R
R"
R'
N
NH2
H+
R=R'= alkyl, aryl and hydrogen
R=R'
R
H
R"
N
reduction
R'
N-substituted imine
R
R"
R'
Synthesis of Amines via reduction
Tertiary amines via reductive amination:
a secondary amine
R"
O
R
R"
R'
R"
N
NH
+
R
R"
R"
N
reduction
R'
R
R"
R'
H
R=R'= alkyl, aryl and hydrogen
R=R'
iminium salt
Since many iminium salts are unstable they are generally not isolate.
As a result the reducing agent is added to the reaction mixture so
that the iminium salt can be reduced as it is formed. Only very weak
reducing agents can be used in this reaction to avoid reduction of the
starting aldehyde or ketone.
Sodium triacetoxyborohydride and sodium cyanoborohydride will
reduce the iminium salt without reducing the carbonyl compound.
Industrially, the reaction is done using hydrogen and a Ni catalyst.
Synthesis of Amines via reduction
Propose a synthetic route for the following.
NH
C18H37NH2
N
C18H37N(CH3)2
H
C18H37NH2
O
C18H37NCH2CH(CH2CH3)CH2CH2CH2CH3
NH2
cpd with no more
than 5 carbons
Br
NH2
N
Synthesis of Amines via acylation reduction
Amines are mono acylated by treatment with with an acid
chloride. Since the resulting amide is a poor nucleophile
multiply acylations are not likely. The amide is then converted
to the amine by treatment with LAH. The type of amine
produced depends on the type of starting amine used.
Starting amine
Ammonia
1° amines
2° amines
product
1° amines
2° amines
3° amines
Synthesis of Amines via acylation reduction
H
CH2CH2CH2CH3
N
from aniline
Synthesis of of primary Amines
Direct alkylation:
Primary amines can be prepared from alkyl halide by using
a large excess of ammonia to avoid / minimize multiply
alkylations on nitrogen.
Gabriel synthesis:
This synthetic method allows for the selective preparation
of primary amines with out the use of a large excess of
amine. The synthesis involved the alkylation of the
phthalimide anion, which is simply a protected ammonia
that can only be alkylated once.
Synthesis of primary Amines (Gabriel Synthesis)
excess NH3
R CH2 X
X= Cl, Br and I
R CH2 NH2
Synthesis from azides and nitriles
The azide and nitrile groups can be reduced to
primary amines using either LAH or catalytic
hydrogenation.
The azide ion N3- and cyanide ion CN- are both very
good nucleophiles that will react readily with primary
and secondary halides.
Synthesis from azides and nitriles
Reaction of an alkyl halide with azide ion produces an
alkyl azide. Reduction of the azide gives corresponding
the 1° amine. The main drawback to the synthetic
method is that alkyl azides are explosive. The net
reaction is the replacement of the halide with NH2.
Synthesis from azides and nitriles
Reaction of an alkyl halide with cyanide ion produces an
a nitrile. Nitriles are very stable and are easily handled.
Reduction of the nitrile gives a primary amine that is
one carbon (CH2) longer then the initial alkyl halide.
CN
CH2Br
-
1) LAH
CH2C N
CH2CH2NH2
2) H2O
Synthesis from nitro compounds
The nitro group can be reduced to the amine by:
1) catalytic hydrogenation
2) active metal and H+
NH2
NO2
H2
CH3
CH3
Ni
90%
Hofmann rearrangement
The Hofmann rearrangement allows for the preparation of
primary amines that have 1°, 2° and 3° alkyl groups, or aryl
amines. The reaction involves the treatment of an amide
with a halogen under strongly basic conditions. This
results in a rearrangement of the amide to an amine in
which the carbonyl of the starting amide has been lost.
CH3 O
C
CH3
Cl2 / OH
C NH2
H2O
-
CH3
C NH2
CH3
Hofmann rearrangement
Hofmann rearrangement