Amines
Nitrogen-Based Functional Groups
Amines as Pharmaceutical Agents
22.1
Amine Nomenclature
The Naming of Parts
Alkylamines
Nitrogen atom is
attached to alkyl group:
Arylamines
Nitrogen atom is
attached to aryl group:
Nomenclature of Primary Alkylamines (RNH2)
Two IUPAC styles
1) analogous to alcohols: replace -e
ending by -anamine
2) name alkyl group and attach -amine
as a suffix
Nomenclature of Primary Alkylamines
n-propylamine
or
propanamine
cyclopropylamine
or
cyclopetanamine
2-bromo-3-chlorobutylamine
Nomenclature of Arylamines (ArNH2)
These compounds are named as derivatives of aniline
aniline
2,4-dibromoaniline
4-bromo-2-ethylaniline
Amino Groups have Lower Priority than Alcohols
With regards to nomenclature, amines rank lower than
alcohols and are named as substituents:
aminoethanol
p-aminobenzoic acid
Secondary and Tertiary Amines
Name
as
N-substituted
derivatives
of
parent
primary amine. The longest chain takes the root name.
N,N-diisopropylethylamine
(a.k.a. Hünig’s base)
4-bromo-N,N-dimethyl-2-methylaniline
Ammonium Salts (R4-nHnN+ X-)
Nitrogen atoms are positively charged when bonded to four
substituents. The root name in this case is the ammonium
ion (NH4+). Remember to name as a salt - two words.
methylammonium acetate
N-ethyl-N-methylbenzylammonium chloride
Quaternary Ammonium Salts (R4N+ X-)
Nitrogen atoms are positively charged when bonded to four
substituents: when all of these substituents are carbon, the
molecule is referred to as a quaternary ammonium ion.
tetrabutylammonium fluoride
(TBAF)
Quaternary ammonium salts
are relatively soluble in
organic
solvents
and
consequently are used as
phase transfer catalysts
benzyltrimethylammonium hydroxide
22.2
Structure and Bonding of Amines
Structure of Alkylamines
147 pm
112°
106°
Alkylamines - Distribution of Electron Density
Note the high electron density on the nitrogen atom. The
chemistry of amines is dominated by reactivity of the lone
pair on this atom. Amines behave as nucleophiles and
Bronsted bases.
Alkylamines - Hydridization at Nitrogen
The hybridization adopted by nitrogen depends upon
the nature of the N-substituents.
Compare methylamine and formamide:
Amines & Amides - Geometry at Nitrogen
the hybridization adopted by nitrogen depends upon the
nature of the N-substituents - compare methylamine
and formamide.
Amines - Geometry at Nitrogen
Angle that the C—N bond makes with bisector of
H—N—H angle is a measure of the pyramidalization at
nitrogen.
sp3
sp2
180°
~125°
142.5°
Amines - Geometry at Nitrogen
Angle that the C—N bond makes with bisector of
H—N—H angle is a measure of the pyramidalization at
nitrogen.
142.5°
Geometry at the nitrogen atom in
aniline is pyramidal;
closer to
methylamine than to formamide.
Geometry of Aniline
The hybridization of the nitrogen atom in aniline lies between
sp2 and sp3
1)
Delocalization of the nitrogen lone pair into the aromatic ring is
most effective if the nitrogen atom is sp2-hybridized and planar.
2)
A planar nitrogen atom increases repulsion between filled lone
pair orbital and p-system of aromatic ring - sp3 hybridization
reduces this “bad” interaction.
142.5°
Aniline - Distribution of Electron Density
Enforce a non-planar
geometry (sp3-like) at the
nitrogen center
Enforce a planar geometry
(sp2-like) at the nitrogen
center
- highest negative potential
is on nitrogen.
- negative potential is
shared by both nitrogen and
ring.
22.3
Physical Properties of Amines
Amines - Physical Properties
Amines are more polar and have higher boiling
points than alkanes;
but are less polar and
have lower boiling points than alcohols.
CH3CH2CH3 CH3CH2NH2 CH3CH2OH
dipole
moment ():
boiling point:
0D
-42°C
1.2 D
1.7 D
17°C
78°C
Amines - Physical Properties
CH3CH2CH2NH2 CH3CH2NHCH3
boiling
point:
50°C
(CH3)3N
34°C
Boiling points of isomeric amines decrease
going from primary to secondary to tertiary amines.
3°C
in
Primary amines have two hydrogens on nitrogen capable
of
being
involved
in
intermolecular
hydrogen
bonding.
Secondary amines have one. Tertiary
amines
cannot
be
involved
in
intermolecular
hydrogen bonds.
22.4
Basicity of Amines
Amines are Brønstead Bases and Nucleophiles
Brønstead Basicity of Amines
1. Alkylamines are slightly stronger
bases than ammonia.
2. ……
Basicity of Amines in Aqueous Solution
The ethylammonium ion (CH3CH2NH3+) is a
weaker acid than ammonium (NH4+)
therefore; ethylamine (H3CH2NH2) is a
stronger base than ammonia (NH3)
The Relationship between pKa and Basicity
The ethylammonium ion (CH3CH2NH3+) is a
weaker acid than ammonium (NH4+)
therefore; ethylamine (H3CH2NH2) is a
stronger base than ammonia (NH3)
The Relationship Between Basicity and Structure
1. Alkylamines are slightly stronger
bases than ammonia.
2. Alkylamines differ very little in
basicity.
Basicity of Amines in Aqueous Solution
The Relationship Between Basicity and Structure
1. Alkylamines are slightly stronger
bases than ammonia.
2. Alkylamines differ very little in
basicity.
3. Arylamines are much weaker
bases than ammonia.
Basicity of Amines in Aqueous Solution
Amine
Conjugate
Acid
pKa
NH3
NH4+
9.3
CH3CH2NH2
CH3CH2NH3+
10.8
(CH3CH2)2NH (CH3CH2)2NH2+
11.1
(CH3CH2)3N
(CH3CH2)3NH+
10.8
PhNH2
PhNH3+
4.6
Arylamines are Relatively Weak Brønstead Bases
Anilinium Ion
Arylamines are Relatively Weak Brønstead Bases
Increasing delocalization
makes diphenylamine a
weaker
base
than
aniline,
and
triphenylamine a weaker
base
than
diphenylamine.
Arylamines - Effect of Substituents on Basicity
1. Alkyl groups on the ring increase basicity by only one 1 pK
unit.
Arylamines - Effect of Substituents on Basicity
2. Electron withdrawing groups, especially ortho
and/or para to amine group, decrease basicity
and can have a large effect.
H
pKa of
conjugate
acid
4.6
CN
3.5
NO2
1.0
X
Basicity of Arylamines - p-Nitroaniline
Lone pair on amine nitrogen is conjugated with
p-nitro group—more delocalized than in aniline
itself. This delocalization is lost upon protonation.
Electron Withdrawing Effects are Cumulative
Electron Withdrawing Effects are Cumulative
Heterocyclic Amines
piperidine
pyridine
pKa of conjugate acid:
11.2
pKa of conjugate acid:
5.2
(an alkylamine)
(resembles an
arylamine in
basicity)
Heterocyclic Amines
imidazole
pyridine
pKa of conjugate acid:
7.0
pKa of conjugate acid:
5.2
Protonation of Imidazole
q. Which nitrogen is protonated in imidazole?
Protonation of Imidazole - Resonance Picture
Protonation in the direction shown gives a
stabilized ion.
The Term ‘Alkaloid’
The term ‘alkaloid’ is composed from two
words, the Arabic ‘al-qualja’ (plant ashes)
and the Greek ‘eidos’ (type, similarity).
The Term ‘Alkaloid’
Meissner 1819: To me it seems wholly
appropriate to refer to those plant
substances currently known by the names of
alkalis, but alkaloids, since some of their
properties they differ from alkalis
considerably, and would thus find their place
before the plant acids in the field of plant
chemistry.
Jacobsen 1882: The bodies referred to as
alkaloids are nitrogen-containing organic
bases. The group, however, is in many
respects not sharply defined.
The Term ‘Alkaloid’
Pelletier 1983: An alkaloid is a cyclic organic
compound containing nitrogen in a negative
oxidation state, which is of limited distribution
among living organisms.
Amines as Natural Products - Alkaloids
The man…. laid his hands on him and after a
while examined his feet and legs, then pinched his
foot hard and asked if he felt it. He said ‘No’; then
after that, his thighs; and passing upwards in this
way he showed us that he was growing cold and
rigid. And then again he touched him and said that
when it reached his heart, he would be gone. The
chill had now reached the region about the groin,
...the attendant uncovered him; his eyes were
fixed. And Crito when he saw it, closed his mouth
and eyes.
[Plato's description of the death of Socrates, as
witnessed by Crito in 399 B.C.]
Conium maculatum
Hemlock contains the alkaloid
coniine, among other compounds
The Toxic Alkaloids of Conium maculatum
Reduction of Nitroarenes - Example
Aromatic nitro compounds are easy to prepare and are readily
reduced to the corresponding anilines under a wide range of
conditions.
Reduction of Nitroarenes - Example
18.9
The Aldol Condensation
Aldol Condensation
Aldol Condensation of Butanal
Dehydration of Aldol Addition Product
C
C
O
H
C
C
C
OH
dehydration of -hydroxy aldehyde can be
catalyzed by either acids or bases
C
O
Dehydration of Aldol Addition Product
C
O
H
NaOH
C
C
OH
in base, the enolate is formed
–
C
O
C
OH
C ••
Dehydration of Aldol Addition Product
C
O
H
NaOH
C
C
OH
the enolate loses hydroxide to form the
,-unsaturated aldehyde
–
C
O
C
OH
C ••
Aldol reactions of ketones
the equilibrium constant for aldol addition
reactions of ketones is usually unfavorable
Termite Self-Defense!
Diethyl Zinc and Deacidification of Brittle Books
14.13
Carbenes and Carbenoids
Carbene
name to give to species that contains a
divalent carbon (carbon with two bonds
and six electrons)
••
C
Br
Br
dibromocarbene
Carbenes are very reactive; normally cannot be
isolated and stored.
Are intermediates in certain reactions.
Generation of Dibromocarbene
Br
Br
H
C
+
– ••
•• OC(CH3)3
••
Br
Br
Br
C ••
Br
–
+
H
••
OC(CH3)3
••
Generation of Dibromocarbene
••
C
Br
Br
Br
Br
C ••
Br
–
+
Br
–
Carbenes react with alkenes
to give cyclopropanes
KOC(CH3)3
Br
(CH3)3COH
Br
+ CHBr3
CBr2 is a highly reactive
(shortlived) intermediate
(75%)
Why the synthesis of
cyclopropanes is important?
Chrysanthemum cinerariaefolium
Why the synthesis of
cyclopropanes is important?
20.7
Sources of Esters
Esters are Commonly Found in Natural Products
3-methylbutyl acetate
also called "isopentyl acetate" and "isoamyl
acetate"
contributes to characteristic odor of bananas
Esters of Glycerol
R, R', and R" can be the same or different
called "triacylglycerols," "glyceryl triesters," or
"triglycerides"
fats and oils are mixtures of glyceryl triesters
Fat & Oil are Mixtures of Glyceryl Triesters
Tristearin: found in many
animal and vegetable fats
Lactones are Cyclic Esters
O
O
CH2(CH2)6CH3
H
H
(Z)-5-Tetradecen-4-olide
(sex pheromone of female Japanese beetle)