Download CHEM 494 Lecture 10b - UIC Department of Chemistry

Amines
Nitrogen-Based Functional Groups!
O
N+
O–
R
N
N
N
azides
R
C
N
nitriles
nitroarenes
N
O
R'
R
R
R''
imines
N
R''
amides
R'
R'
R
N
R''
amines
Amines as Pharmaceutical Agents!
O
OH
HN
CH3
CH3
HN
CH3
Pseudoephedrine
(decongestant)
OH
Acetaminophen
(analgesic)
NH2
Cl
O
H
N
OH
N
N
O
O
O
CH3
Aspartame
(artificial sweetener)
Chlorpheniramine
(blocks the effect of histamine)
22.1
Amine Nomenclature
The Naming of Parts!
Alkylamines
R
N
Nitrogen atom is
attached to alkyl group:
Arylamines
Nitrogen atom is
attached to aryl group:
Alkyl
R
R = H or Alkyl
R
N
R
R = H, Alkyl or Aryl
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
H3C
H2
C
C
H2
n-propylamine
or
propanamine
H
N
H
H
cyclopropylamine
or
cyclopetanamine
N
H
Br
H3C
H
N
H
Cl
2-bromo-3-chlorobutylamine
Nomenclature of Arylamines (ArNH2)
These compounds are named as derivatives of aniline
H
N
aniline
H
Br
H
N
H
Br
2,4-dibromoaniline
H
N
H
Br
CH3
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:
OH
H2N
aminoethanol
O
OH
H2N
p-aminobenzoic acid
Secondary and Tertiary Amines
Name as N-substituted derivatives of parent
primary amine. The longest chain takes the root name.
CH3
H3C
CH3
CH3
N
N,N-diisopropylethylamine
(a.k.a. Hünig’s base)
CH3
CH3
CH3
N
CH3
4-bromo-N,N-dimethyl-2-methylaniline
Br
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.
H
N
H3C
H
O
methylammonium acetate
H
O
CH3
N
CH3 Cl
H
CH3
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.
C4H9
N
C4H9
C4H9
F
C4H9
N
CH3
tetrabutylammonium fluoride
(TBAF)
CH3
CH3
OH
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:
formamide
methylamine
H
H
O
H
C
H
N
N
H
H
H
H
Lone Pair
H
H
sp3-hydridized
tetrahedral
N
H
H
H
Lone Pair
O
C
N
H
H
H
sp2-hydridized
planar
Amines & Amides - Geometry at Nitrogen
the hybridization adopted by nitrogen depends upon the
nature of the N-substituents - compare methylamine
and formamide.
formamide
methylamine
H
H
O
H
C
H
N
N
H
H
H
H
Lone Pair
H
H
sp3-hydridized
tetrahedral
N
H
H
H
Lone Pair
O
C
N
H
H
H
sp2-hydridized
planar
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 π-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 (µ):
0D
1.2 D
1.7 D
boiling point:
-42°C
17°C
78°C
Amines - Physical Properties
CH3CH2CH2NH2 CH3CH2NHCH3
boiling
point:
50°C
34°C
(CH3)3N
3°C
Boiling points of isomeric amines decrease in
going from primary to secondary to tertiary amines.
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
N
H
X
N
X
Amines behave as
Nucleophiles
Amines behave as
Brønstead Bases
Amines are electron-rich and
have a reactive lone pair, which
can form a covalent bond to
electrophiles
C
N
C
Amines behave as
Nucleophiles
O
Brønstead Basicity of Amines
1. Alkylamines are slightly stronger
bases than ammonia.
2. ……
Basicity of Amines in Aqueous Solution
Amine
Conjugate
Acid
H
H
N
N
H
H
H
N
9.3
H
H
H
H3C
H
pKa
H3C
H
N
H
H
10.8
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
Amine
Conjugate
Acid
H
H
N
N
H
H
H
N
9.3
H
H
H
H3C
H
pKa
H3C
H
N
H
H
10.8
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
Amine
Conjugate
Acid
H
H
N
N
H
H
H
H
N
H3C
N
H
N
H
H
H
10.8
H
H
H3C
9.3
H
H
H3C
pKa
CH3
H3C
N
CH3 11.1
H
CH3
CH3
H3C
N
CH3
H3C
N
H
CH3 10.8
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
Stronger
H
Acid
N
H
H
H
Anilinium Ion
Stronger
Base
N
H
pKa = 4.6
Weaker
Base
H
N
H
H
H
Weaker
Acid
N
H
pKa = 10.6
Arylamines are Relatively Weak Brønstead Bases
Increasing delocalization
makes diphenylamine a
weaker base than
a n i l i n e , a n d
triphenylamine a weaker
b a s e
t h a n
diphenylamine.
Amine
Conjugate
Acid
H
H
N
N
H
H
H
H
N
N
H
N
H
N
H
pKa
4.6
0.8
~ -5.0
Arylamines - Effect of Substituents on Basicity
1. Alkyl groups on the ring increase basicity by only one 1 pK
unit.
Conjugate
Acid
Amine
H
H
N
N
H
H
H
H
H3C
pKa
4.6
H
H
H
N
N
H
H
H
H3C
5.3
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
H
N
X
H
N
H
H
H
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.
O
O
N
O
N
H
H
H
N
O
N
H
Electron Withdrawing Effects are Cumulative
H
H
N
N
H
is 3800 times
more basic than.......
H
O2N
H
p-nitroaniline
aniline
NO2
H
N
H
is 1,000, 000, 000 times
more basic than.......
H
N
O2N
H
aniline
2,4-dinitroaniline
H
Electron Withdrawing Effects are Cumulative
Conjugate
Acid
Amine
H
N
H
H
N
N
H
H
pKa
H
10.
3
H
N
8.3
H
N
N
H
3.1
Heterocyclic Amines
is more
basic than......
N
N
H
piperidine
pyridine
pKa of conjugate acid:
11.2
pKa of conjugate acid:
5.2
(an alkylamine)
(resembles an
arylamine in
basicity)
Heterocyclic Amines
N
N
H
is more
basic than......
N
imidazole
pyridine
pKa of conjugate acid:
7.0
pKa of conjugate acid:
5.2
Protonation of Imidazole
q. Which nitrogen is protonated in imidazole?
N
N
N
N
H
H
H+
H+
H
H
N
N
H
aromatic
imidazolium
ion
N
N
H
nonaromatic
iminium
ion
Protonation of Imidazole - Resonance Picture
Protonation in the direction shown gives a
stabilized ion.
N
N
H
H+
H
N
N
H
aromatic
imidazolium
ion
H
N
N
H
aromatic
imidazolium
ion
The Term ‘Alkaloid’!
The term ‘alkaloid’ is composed from two
words, the Arabic ‘al-qualja’ (plant ashes)
and the Greek ‘ειδοσ’ (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.
OCH3
H3C
N
OH
H
HO
H
N
O
O
(-)-Hyoscyamine
(Atropa belladonna)
N
H
(-)-Quinine
(Cinchona pubescens)
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
N
N
H
N
H
2-Methylpiperidine
γ-Coniceine
Coniine
HO
H
HO
H
N
H
(+)-Pseudoconhydrine
N
H
O
Conhydrinone
N
Me
(+)-N-Methylpseudoconhydrine
H
N
N
H
OH
(+)-α-Conhydrine
Me
N-Methylconiine
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.
O
O
OCH3
OH
OCH3
Combretastatin A-2
a antineoplastic agent
isloated from the South
African bush willow tree
Reduction of Nitroarenes - Example
O
Br
PPh3
O
O
Ph
P
Ph
O
OCH3
H
H
H
Ph
n-BuLi
Br
O
Ph
O
ylide
(reactive nucleophile) OCH3
OCH3
Ph
P
O
Ph
H
phosphonium
salt
Wittig Reaction
NO2
OCH3
O
Reduction
O
Zinc metal
O
acetic acid
OCH3
N
OCH3 H
H
O
OCH3
NO2
OCH3
18.9
The Aldol Condensation
Aldol Condensation
O
OH
KOH
H2O
R
H
H
H
Aldol Addition
Reaction
β
O
H
R
H
α
R
Heat
KOH
Heat, -H2O
Dehydration
Aldol Condensation
Reaction
O
β
R
α
H
R
Dehydration Product
Aldol Condensation of Butanal
newly formed
carbon-carbon double bond
KOH
H2O
O
H
2 x n-Butanal
100 °C
(86%)
Aldol Condensation
Reaction
O
β
α
H
α,β-Unsaturated Ketone
Dehydration of Aldol Addition Product
C
H
C
O
C
C
C
OH
dehydration of β-hydroxy aldehyde can be
catalyzed by either acids or bases
C
O
Dehydration of Aldol Addition Product
C
H
O
NaOH
C
C
OH
in base, the enolate is formed
–
C
O
C
OH
C ••
Dehydration of Aldol Addition Product
C
H
O
NaOH
C
C
OH
the enolate loses hydroxide to form the
α,β-unsaturated aldehyde
–
C
O
C
OH
C ••
Aldol reactions of ketones
O
H3C
CH3
2 x Acetone
OH
2%
H3C
98%
H3C
O
CH3
Formation of Aldol product is not
thermodynamically favorable
[4-hydroxy-4-methylpentan-2-one]
the equilibrium constant for aldol addition
reactions of ketones is usually unfavorable
Termite Self-Defense!
Toxic compound produced by soldier termites
of the species Schedorhinotermes lamanianus
nucleophilic
alkenes are not
reactive to
nucleophiles
conjugated
alkene is
reduced by
enyzme
expressed by
worker termites
O
electrophilic
alkene reacts with
nucleophilic thiols
(RSH)
O
Non-toxic to worker termiotes
Diethyl Zinc and Deacidification of Brittle Books
Me
Zn
Me
Diethylzinc (a volatile liquid)
H2O (in paper)
Ethane
(a volatile gas)
CH3 CH3
+
Zn(OH)2
CO2
Zn(CO3)
Unused zinc hydroxide
reacts with carbon dioxide
form zinc carbonate
Zinc hydroxide
neutralizes acid (H+)
in paper
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?
R
Me
Me
O
O
Me
Me
O
Me
Pyrethrin
(Natural Insecticide in
RAIDTM)
Chrysanthemum cinerariaefolium
Why the synthesis of
cyclopropanes is important?
Cl
O
H
CN
O
Cl
Me
Me
Cypermetrin is an insecticide
with contact and stomach
action and is highly effective
against a wide range of chewing
and sucking insects in various
crops. It is also active against
mosquit.oes
O
20.7
Sources of Esters
Esters are Commonly Found in Natural Products!
O
CH3
CH3
O
CH3
3-methylbutyl acetate
also called "isopentyl acetate" and "isoamyl acetate"
contributes to characteristic odor of bananas
Esters of Glycerol!
O
R'
O
O
R
O
O
R''
O
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 !
O
(CH2)16CH3
O
O
CH3(CH2)16
O
O
(CH2)16CH3
O
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)