2. Introduction
Ethers are compounds of formula R-O-R
H O H C
2
H
5O
H C
2
H
5
O
C
2
H
5
Physical Properties of Ethers
Structure and Polarity of Ethers
Boiling Points of Ethers; Hydrogen Bonding
Ethers are nonhydroxylic (no hydroxyl group), and they
are normally unreactive toward strong bases
Ethers
3. Nomenclature of Ethers
Common Names (Alkyl Alkyl Ether Names)
IUPAC Names (Alkoxy Alkane Names)
H
3
C
O
C
2
H
5 O
C
H
3 C
l
H
2
C
O
C
H
3
Methoxyethane
Ethyl methyl ether
Chloromethoxymethane
Chloromethyl methyl ether
Methyl phenyl ether
Methoxybenzene
C
H
3
H
3
C
O
C
2
H
5
C
l
O
C
H
3
C H 2 O H
C H 2 O C 2 H 5
2-ethoxyethanol
1-chloro-2-methoxycyclobutane
3-ethoxy-1,1-dimethylcyclohexane
4. The Williamson Ether Synthesis
O
H
N
a
C
H
3
I
O
C
H
3
N
a
H
3
C
C
H
2
C
H
2
O
H
+
H
3
C
B
rH
3
C
C
H
2
C
H
2
O
C
H
3
Substitution
reaction
N
a
O
H O
N
a
+
C
H
3
I
O
C
H
3
N
a
I
Remember: alkane that
bonded to halogen has a
positive charge
5. Synthesis of Ethers by Alkoxymercuration–Demercuration
H3C C
H
CHCH3
Hg(OAc)2
CH3OH
H3C C CHCH3
H
H OCH3
Bimolecular Condensation of Alcohols
C
2
H
5
O
HC
2
H
5
O
C
2
H
5
H
2
S
O
4
Addition
reaction
Remember: Sulphuric
acid absorbs water
6. Show how you would use the Williamson ether synthesis to prepare the
following
(a) Cyclohexyl propyl ether (b) isopropyl methyl ether
(C) 1-methoxy-4-nitrobenzene (d) ethyl n-propyl ether
Give a common name (when possible) and a systematic name for
each compound.
C
2
H
5
O
C
H
(
C
H
3
)
2
O C H 3
O C H 3 O
C
H
3
7. Aldehyde can easily oxidize and reactive toward
nucleophilic addition
Nomenclature of aldehyde
formaldehyde acetaldehyde propionaldehyde
Benzaldehyde
2-phenylacetaldehyde
Methanal Propanal
Ethanal
2-phenylethanal
RC
O
H R C
O
R
Aldehyde ketone
Sp2
C
O
C
O
HC
O
H H
3
C
C
O
H H
3
C
H
2
C
C
O
H
H
3
C
C
H
H
2
C
C
O
H
O
H
3-hydroxybutanal
H
2
C
C
H
2
C
C
O
H
H
3
C
O
3-oxopentanal
C
H
O C
H
2
C
H
O
7
8. Propan-2-one
Acetone
Butan-2-one
Methyl ethyl ketone
3-methylbutan-2-one
Methyl isopropyl ketone
1-phenylpropan-2-one
Benzyl methyl ketone
Nomenclature of ketone
H
3
C
C
O
C
H
3 H
3
C
C
O
C
H
2
C
H
3 H
3
C
C
O
C
H
C
H
3
C
H
3
H
2
C
C
O
C
H
3
O
cyclohex-2-en-1-one
H
3
C
C
O
H
2
C
C
C
H
3
O
H
C
H
3
4-hydroxy-4-methyl-
pentan-2-one
8
Remember
10. Preparation of aldehyde
Oxidation of primary alcohol
Ethanol Acetaldehyde
10
H
3
C
C
H
2
O
H
K
2
C
r
2
O
7
H
3
C
C
H
O
Aldehydes from Ozonolysis of Alkenes
H
2
C
C
H
C
H
3 O
3 C
O
H
H
C
O
H
C
H
3
+ +
(
C
H
3
)
2
S
Alcohol oxidizes to aldehyde
Aldehyde oxidizes to carboxylic acid
Ozone break the double
bond and form aldehyde.
12. Oxidation of secondary alcohol
Preparation of Ketone
H
3
CC K
2
C
r
2
O
7 H
3
CC
C
H
3
O
H
H
O
C
H
3
propan-2-ol propan-2-one
Friedel crafts acylation
C
C
O
C
l
A
r
H
A
l
C
l
3
O
benzophenone
12
In the presence of the catalyst, the
reaction occur at the aromatic ring
13. Reaction of acid chloride with organocadmium compounds
13
H 3 C C
O
H C 2 H 5 M g C l
H 3 C C
H
C 2 H 5
O M g C l H 3 C C
H
C 2 H 5
O H
H 2 O
K 2 C r 2 O 7
H 3 C C
O
C 2 H 5
H 3 C C
H
C 2 H 5
O H
C
C O C l
O
B r M g
C d C l 2 C d
2
C d
2
+
Grignard reagent
Remember: alkane that
bonded to metal has a
negative charge
14. H 3 C C H O
H 3 C C O O H
A g ( N H 3 ) 2 O H +
+ A g N H 3 H 2 O
+
K M n O 4 H 3 C C O O H
H 3 C C O O H
K 2 C r 2 O 7
Oxidation
Tollens test
Haloform reaction
+
H
3
C
C
O
C
H
3 K
O
C
l H
3
C
C
O
O
KC
H
I
3
+
I
o
d
o
f
o
r
m
Oxidation occur in the
aldehyde not in ketone
Reaction of aldehyde and ketone
14
15. Reduction to alcohol
Reduction to hydrocarbons
C
O
C
H
2
C
H
2
C
H
3
P
h
e
n
y
l
n
-
p
r
o
p
y
l
k
e
t
o
n
e
Z
n
(
H
g
)
2
C
o
n
.
H
2
S
O
4
H
2
C
C
H
2
C
H
2
C
H
3
B
u
t
y
l
b
e
n
z
e
n
e
O
N
H
2
N
H
2
b
a
s
e
C
y
c
l
o
p
e
n
t
a
n
o
n
e
c
y
c
l
o
p
e
n
t
a
n
e
H
3
C
C
O
C
H
3
L
i
A
l
H
4
H
3
C
C
H
H
C
H
3
O
H
O
O
H
N
i
,
H
2
Clemmensen reduction
Welff-Kishner reduction
15
Remember: the reaction
depends on the catalyst
16. Addition of Grignard reagent
H
3
C
C
O
C
H
3
C
2
H
5
M
g
C
l H
3
C
C
C
H
3
C
2
H
5
O
M
g
C
l
H
3
C
C
C
H
3
C
2
H
5
O
H
H
2
O
Addition of cyanide: cyanohydrin formation
H
3
C
C
O
C
H
3
N
a
C
N H
3
C
C
C
H
3
C
N
O
H
N
a
H
S
O
4
H
3
C
C
C
H
3
C
O
O
H
O
H
2
-
h
y
d
r
o
x
y
-
2
-
m
e
t
h
y
l
p
r
o
p
a
n
e
n
i
t
r
i
l
e 2
-
h
y
d
r
o
x
y
-
2
-
m
e
t
h
y
l
p
r
o
p
a
n
o
i
c
a
c
i
d
H
2
O
H
H
3
C
C
O
C
H
3
N
a
C
N H
3
C
C
C
H
3
C
N
O
H
N
a
H
S
O
4
H
3
C
C
C
H
3
C
O
O
H
O
H
2
-
h
y
d
r
o
x
y
-
2
-
m
e
t
h
y
l
p
r
o
p
a
n
e
n
i
t
r
i
l
e 2
-
h
y
d
r
o
x
y
-
2
-
m
e
t
h
y
l
p
r
o
p
a
n
o
i
c
a
c
i
d
H
2
O
H
H
2
C
C
C
H
3
C
O
O
H
2-methyl-2-propenoic acid
methacrylic acid
16
Hydrolysis reaction
17. Addition of derivatives of ammonia
C
O
H
2
N
G
C
O
H
H
N
G C
N
G
H
2
O
+
+
H
2
N O
H
H
2
N N
H
2
H
2
N N
H
C
6
H
5
H
2
N N
H
C
O
N
H
2
CN
O
H
CN
N
H
2
CN
N
H
C
6
H
5
CN
N
H
C
O
N
H
2
O
x
im
e
H
y
drazo
n
e
P
heny
lh
y
drazo
n
e
S
em
icarb
azon
e
H
y
d
ox
y
lam
in
e
H
y
d
razin
e
P
heny
lh
y
drazin
e
S
em
icarbazide
17
18. Addition of alcohol: Acetal formation
H
3
CC
H
O
C
2
H
5
O
H
H
C
l
H
3
CC
H
O
C
2
H
5
O
C
2
H
5
+ A
c
e
t
a
l
d
e
h
y
d
ed
i
e
t
h
y
l
e
c
a
t
a
l
18
Halogenation of ketone
C
O
C C
O
C
X
X 2
+
B a s e o r a c i d
H X
+
α-Halogenation
19. Cannizzaro reaction
C
H
O
C
l
C
O
O
C
l
C
H
2
O
H
C
l
+
m
-
C
h
l
o
r
o
b
e
n
z
a
l
d
e
h
y
d
e m
-
C
h
l
o
r
o
b
e
n
z
o
a
t
e
i
o
n m
-
C
h
l
o
r
o
b
e
n
z
y
la
l
c
o
h
o
l
2
K
O
H
CHO
OCH3
+
NaOH
HCHO +
OCH3
CH2OH
OCH3
OCH3
HCOO
(3,4-dimethoxyphenyl)methanol
3,4-Dimethoxybenzyl alcohol
Oxidation and reduction reaction
Compound should not contains an α-hydrogen
If contains α-hydrogen in the aldehyde so aldol condensation will form
19
20. 20
Predict the products formed when cyclohexanecarbaldehyde reacts with
the following reagents.
(a) PhMgBr, then H3O+ (b) Tollens reagent (c) semicarbazide and weak acid
Show how you would synthesize octanal from each compound. You may use any
necessary reagents.
(a) octan-1-ol (b) non-1-ene (c) 1-bromohexane
21. C
O
OH R C
O
OH R COOH R CO2H
carboxyl group carboxylic acid condensed structures
H
C
O
O
H C
O
O
H C
O
O
H
f
o
r
m
i
c
a
c
i
d
o
c
t
a
n
o
i
c
a
c
i
d b
e
n
z
o
i
c
a
c
i
d
m
e
t
h
a
n
o
i
c
a
c
i
d
Introduction
Fatty acids
Dr. Arwa Alshargabi 21
Carboxylic acid and their Derivatives
22. C
O
O
H
H
3C
H
C
C
H
3
C
O
O
H
H
3
C C
O
O
H
Pent-2-enoic acid 2-methylpropanoic acid 4,6-dimethylnonanoic acid
C
O
O
H
α
β
γ
δ
ε
C
O
2
H
N
H
2
α
β
γ
H
3
C
H
C
C
H
3
C
O
O
H
α
α- methylpropanoic acid
2-methylpropanoic acid
β - chlorohexanoic acid
C
O
2
H
C
l
β
α
3-chlorohexanoic acid
γ- aminohexanoic acid
4- aminohexanoic acid
Nomenclature
Dr. Arwa Alshargabi 22
24. C
O
H
3
C
C
l
Acetyl Chloride
Ethanoyl Chloride
C
O
Cl
Benzoyl Chloride Acetic Anhydride
Ethanoic Anhydride
Benzoic anhydride
C
O
H3C NH2
Acetamide
Ethanamide
C
O
N H 2
Benzamide
C
O
H 3 C O C 2 H 5 C
O
O C 2 H 5
Ethyl Acetate Ethyl Benzoate
Ethyl Ethanoate
C
H
3
C
O
O
C
O
C
H
3
Nomenclature of acid derivatives
O
O
O
Dr. Arwa Alshargabi 24
25. Dr. Arwa Alshargabi 25
Draw the structures of the following carboxylic acids.
(a) α- methylbutyric acid (b) 2-bromobutanoic acid
(c) 4-aminopentanoic acid (d) cis-4-phenylbut-2-enoic acid
(f) 2,3-dimethylfumaric acid (g) m-chlorobenzoic acid
(h) (j)
(k) (l)
O
H
O
O
O
H
O
O
O H
O
O H
O
O
H
O
H
O
C
l
26. Structure and Physical Properties of Carboxylic Acids
R
C
O
H
O
C
O
O
R
H
R
C
O
O
H
R
C
O
O
O
H
H
C
H
3
C
O
O
H C
H
3
C
O
O
N
a
+
N
a
O
H
Sp2
R
C
O
O
H
R
C
O
H
O
Boiling point
Melting Points (single and
double bond)
Solubilities
Acidity
Substituent Effects on
Acidity
H
3
C
C
O
O
H
C
l
H
2
C
C
O
O
H
C
l
2
H
CC
O
O
H
stronger acids
Dr. Arwa Alshargabi 26
28. Hydrolysis of nitriles
Oxidation of primary alcohols
H
3
C
C
H
2
O
H
K
M
n
O
4
H
3
C
C
O
O
H
Carbonation of Grignard reagents
C
C
H
3
C
H
3
H
3
C
C
l C
C
H
3
C
H
3
H
3
C
M
g
C
l C
C
H
3
C
H
3
H
3
C
C
O
O
M
g
X C
C
H
3
C
H
3
H
3
C
C
O
O
H
M
g C
O
2 H
C
N
H
2
O
C
O
O
H
+
a
c
i
d
/
b
a
s
e
Dr. Arwa Alshargabi 28
30. Show how you would synthesize the following carboxylic acids, using the
indicated starting materials.
(a) oct-4-yne to butanoic acid (b) bromobenzene to phenylacetic acid
(c) p-xylene to terephthalic acid (d) butan-2-ol to 2-methylbutanoic acid
(e) trans-cyclodecene to decanedioic acid (f) allyl iodide to but-3- enoic acid
Dr. Arwa Alshargabi 30
31. Derivatives of carboxylic acid
Acetic Anhydride
Ethanoic Anhydride
Benzoic anhydride
C
O
H3C NH2
Acetamide
Ethanamide
C
O
N H 2
Benzamide
C
O
H 3 C O C 2 H 5 C
O
O C 2 H 5
Ethyl Acetate Ethyl Benzoate
Ethyl Ethanoate
C
H
3
C
O
O
C
O
C
H
3
C
O O
C
O
Dr. Arwa Alshargabi 31
C
O
H
3
C
C
l
Acetyl Chloride
Ethanoyl Chloride
C
O
Cl
Benzoyl Chloride
32. Reactions
The Fischer esterification
+
H
3C C
O
O
H
H
3C O
H
H
3C C
O
O C
H
3
H
O
H
O
O
H H
+
O
H
O
O
C
H
3
H
3C O
H
m
ethyl acetate
m
ethyl 2-hydroxybenzoate
Dr. Arwa Alshargabi 32
33. Conversion to acid chloride
R
C
O
C
l
R
C
O
O
H
S
O
C
l
2
P
C
l
3
P
C
l
5
p
r
o
p
i
o
n
y
lc
h
l
o
r
i
d
e
+
O
O
H
+
O
C
l
H
2
CC
O
O
H S
O
C
l
2
P
C
l
5
H
3
C
H
2
CC
O
C
l
H
3
C
b
e
n
z
o
y
lc
h
l
o
r
i
d
e
Dr. Arwa Alshargabi 33
34. Conversion to amide
+
O
O H
+
O
C l
H 2
C C O O H S O C l 2
P C l 5
H 3 C
H 2
C C O C l
H 3 C
O H
N
H 2
C C O N H 2
H 3 C
N H 3
C 2 H 5 N H 2 C 2 H 5
N - e t h y l b e n z a m i d e
p r o p i o n a m i d e
O
H
b e n z a l d e h y d e
b e n z o y l c h l o r i d e
A l ( O - t - B u ) 3
l i t h i u m t r i - t e r t - b u t o x y a l u m i n u m h y d r i d e O
O C H 3
C H 3 O H
m e t h y l b e n z o a t e
Dr. Arwa Alshargabi 34
36. Substitution in alky or aryl group
+
O
OH
+
COOH
H2
C COOH
H3C C
H
COOH
H3C
Br2
H2SO4
Br
HNO3
NO2
C COOH
H3C
Br
Br2
Br
2,2-dibromopropanoic acid
2-bromopropanoic acid
α halogenation
Dr. Arwa Alshargabi 36
37. Dr. Arwa Alshargabi 37
+
H2
C COOH
H3C C
H
COOH
H3C
Br2
Br
C COOH
H3C
NH2
NH3
H
NaOH
C
H
COONa
H3C
OH
C
H
COOH
H3C
OH
H
2-hydroxypropanoic acid
C
H
COOH
H2C
prop-2-enoic acid
-H2O
38. Dr. Arwa Alshargabi 38
Show how to synthesize the following compounds, using appropriate carboxylic
acids
(a) methyl salicylate (b) N,N-dimethylformamide
(c) N,N-diethyl-meta-toluamide (d) 2-phenylacetaldehyde
(e) 2-phenylethanol (f) methyl cyclohexyl ketone
(g) phenyl propionate (h) methyl formate
40. N H 2
C H 3
3-methyl-1-butanamine
H
N
C H 3
C H 3
N-methyl-2-butanamine
H
3
C
N
H
2
Methanamine
Aminobenzene
N
H
2
Aniline
N
H
2
Cyclopent-2-en-1-amine
3-aminocyclopentene
Nomenclature of Amines
Methylamine 3-methyl-1-butaylamine N-methyl-2-butylamine
N
2,4,N,N-tetramethyl-3-hexan-
amine
Dr. Arwa Alshargabi 40
41. H
N H
N
C
O
O
H
H
2
N H
2
N C
O
O
H
N
Diisopentylamine
Cyclohexyldimethylamine Diphenylamine
P-aminobenzoic acid γ-aminobutyric acid
4-aminobutanoic acid
4-aminobenzoic acid
H2N CH2CH2OH
2-aminoethanol
Dr. Arwa Alshargabi 41
42. N H 2
4-(ethylmethylamino)cyclohexanone 3-(dimethylamino)hexan-1-ol
3-aminocyclohexanol
H
2
N
4-methylaniline Or p-toluidine
H 3 C H 2 C N
C H 2 C H 3
C H 2 C H 3
C H 2 C H 3
I
Draw the structures of the following compounds:
Tert-butylamine
N-ethyl-n-methylhexan-3-amine m-chloroaniline
N
H
2
O
H
Dr. Arwa Alshargabi 42
43. Structure and Physical Properties of Amines of Amines
N
Sp3
Basicity of Amines: amine is a nucleophile
Effects on Amine Basicity
Resonance Effects on Basicity
Salts of Amines
Amines are strongly polar, less electronegative than oxygen thus weaker
hydrogen bonds than do alcohols
R
N
H
H
H
3
C
I
+ R
N
C
H
3
H
H
I
+
R NH2 R2 NH
H NH2 <
<
H
3
C
N
H
2
N
H
2
<
N
H
2
+
H
C
l N
H
3
C
l
Dr. Arwa Alshargabi 43
44. Preparation of amines
Reduction of nitro compounds
Ethyl 4-nitrobenzoate Ethyl 4-aminobenzoate
1-nitropropane Propan-1-amine
4-nitrobenzenamine Benzene-1,4-diamine
C
2
H
5
O
O
C
N
O
2
H
2
,
P
t
C
O
O
C
2
H
5
H
2
N
N
O
2
N
H
2
F
e
,
H
C
l
N
H
2
O
2
N
N
H
2
H
2
N
S
n
,
H
C
l
Dr. Arwa Alshargabi 44
45. Reductive amination
Dr. Arwa Alshargabi 45
+
H
O
N
H
2
H
3
C
C
O
C
H
3
L
i
A
l
H
4 H
3
C
C
H
C
H
3
N
H
2
Primary Amines
Secondary Amines
+
C
2
H
5
N
H
2
H
3
C
C
O
H L
i
A
l
H
4 H
3
C
C
H
H
N
H
C
2
H
5
Diethylamine
Tertiary
Amines
+
C
2
H
5
N
H
H
3
C
C
O
H H
3
C
C
H
H
N
C
2
H
5
C
H
3 C
H
3
N
a
B
H
3
C
N
N-ethyl-N-methylethanamine
46. Dr. Arwa Alshargabi 46
Synthesis of Amines by Acylation–Reduction
+
C
2
H
5
N
H
2
H
3
C
C
O
C
l
L
i
A
l
H
4
H
3
C
C
N
H
C
2
H
5 H
3
C
C
H
H
N
H
C
2
H
5
O
+
N
H
3
C
O
C
l
L
i
A
l
H
4
C
N
H
2 C
H
H
N
H
2
O
+
H
N
C
O
C
l
L
i
A
l
H
4
C
N
O
H
3
C
C
H
3
H
2
C
N
C
H
3
Primary Amines
Secondary Amines
Tertiary
Amines
47. Reduction of halide with ammonia or amines
Benzylchloride Benzylamine
Dr. Arwa Alshargabi 47
C
H
2
C
l C
H
2
N
H
2
N
H
3
NH3
CH3COOH H2C
NH2
COONH4 H2C
NH2
COOH
H2C
Cl
COOH H
Cl2
2-chloroacetic acid 2-aminoacetic acid
48. Dr. Arwa Alshargabi 48
Reduction of Azides and Nitriles
C
H
2
C
l C
H
2
C
N
N
a
C
N
C
H
2
C
H
2
N
H
2
H
2
,
N
i
H
3
C
C
H
2
C
l
N
a
N
3 H
2
,
N
i
H
3
C
C
H
2
N
3 H
3
C
C
H
2
N
H
2
Hofmann degradation of amides
C
O
N
H
2 N
H
2
B
r B
r
K
O
B
r
49. Dr. Arwa Alshargabi 49
CH2CN
CH2CH2NH2
H
2 , Ni
2-phenylethanamine
CH2CH2CONH2
KOBr
Ni, H2
CH2CHO
NH3
CH2CH2Cl
NH3
CH2CH2NO2
Fe, HCl
3-phenylpropanamide
2-phenylacetaldehyde
2-phenylacetonitrile
CH2COCl
NH3
LiAlH4
Summary of amines synthesis
50. Dr. Arwa Alshargabi 50
Show how to synthesize the following amines from the indicated starting materials by
reductive amination.
(a) Benzylmethylamine from benzaldehyde (b) N-benzylaniline from aniline
Show how you would prepare the following aromatic amines by aromatic nitration, followed
by reduction. You may use benzene and toluene as your aromatic starting materials.
(a) aniline (b) p-bromoaniline
(c) m-bromoaniline (d) m-aminobenzoic acid
Show how you would accomplish the following synthetic conversions.
(a) benzyl bromide to benzylamine (b) 1-bromo-2-phenylethane to 3-phenylpropan-1-amine
(c) pentanoic acid to pentan-1-amine (d) pentanoic acid to hexan-1-amine
(e) 2-bromobutane to butan-2-amine (f) 2-bromobutane to 2-methylbutan-1-amine
51. Dr. Arwa Alshargabi 51
C H 2C l
+
H 3C N H 2 H 3C
H
N
H 2
C
C H 2C l
C H 3
N
H 2
C
C H 3
N
H 2
C
C H 2
H 2
C
C l
H 3C
H
N
H 2
C +
H 2
C
C H 3
N
H 2
C
H 2
C C H 2C l
+
Alkylation of Amines by Alkyl Halides
Reaction of amines
52. Dr. Arwa Alshargabi 52
Conversion into amides
NH2
(CH3CO)2O N
H
C
O
CH3
N-Phenylacetamide
C6H5SO2Cl
NaOH
N
H
S
O
O
N-Phenylbenzenesulfonamide
H
N
COCl
C
O
N-phenylbenzamide
N
53. Dr. Arwa Alshargabi 53
H 3C N
CH 3
CH 3
CH 2CH 2CH 3O H
H 3C N
CH 3
CH 3
CH 2CH 2CH 3Cl
A g2O
H 3C N
CH 3
CH 3
H 2C CH CH 3 + + H 2O
H 2O
H 3C N
CH 3
CH 2CH 2CH 3Cl CH 3I
H 3C N
CH 3
CH 3
CH 2CH 2CH 3Cl
H 3C N
CH 3
CH 3
CH 2CH 2CH 3O H H eat
Hofmann elimination from quaternary ammonium salts
54. Reaction with nitrous acid
N 2 C l
N H 2
N a N O 2
H C l
C l
C u C l
C u B r
C u C N
B r
C N
C h l o r o b e n z e n e
B r o m o b e n z e n e
C y a n o b e n z e n e
Sandmeyer reaction
N
2C
l
H
B
F
4 H
e
a
t
F
N
2B
F
4
Replacement by F
Dr. Arwa Alshargabi 54
55. Diazonium Salts as reaction
N 2 H S O 4
H 2 S O 4
N a N O 2
K I
H 2 O
H
H 3 P O 2
p
h
e
n
o
l
N a C N
C N
O H
N H 2
N N O H
I
Dr. Arwa Alshargabi 55
56. Dr. Arwa Alshargabi 56
Give the products expected from the following reactions.
acetyl chloride + ethylamine
Predict the major products formed when the following amines undergo exhaustive
methylation, treatment with and heating.
hexan-2-amine
Show how you would convert aniline to the following compounds.
(a) fluorobenzene (b) chlorobenzene
(c) 1,3,5-trimethylbenzene (d) bromobenzene
(e) iodobenzene (f) benzonitrile
57. 57
Heterocyclic Compounds
Heteroatoms are atoms other than carbon or hydrogen that may be present in
organic compounds. The most common heteroatoms are oxygen, nitrogen, and
sulfur. In heterocyclic compounds, one or more of these heteroatoms
replaces carbon in a ring.
Heterocycles can be divided into two subgroups: nonaromatic and aromatic.
Pyridine: Bonding and Basicity
N
N
pyridine is miscible with most organic
solvents and also completely miscible
with water! polar !
weakly basic
react with strong acids
Organic Chemistry 3
58. 58
E t O O C C H 2
O
H 3 C
C O O C H 3
C H 3
H 2 N N
H
E t O O C C O O C H 3
C H 3
H 3 C
+
+
O
Ph
H3C
EtOOC
H2N Ph
O
N
H
Ph
Ph
EtOOC
H3C
O
O
R
1
O
R
N
H
3
N
R
R
1
β‐ketoester
Pyridines – Synthesis
Organic Chemistry 3
59. 59
Substitution in Pyridine
When substitution does occur, electrophiles attack pyridine mainly at C-3,
whereas the nucleophilic attack happen at C2, C4 and C6
N
N
N N N
1
2
4
3
5
6
H 2 S O 4
H N O 3
N a N H 2
N
N
N O 2
N H 2
Organic Chemistry 3
60. 60
N H 2 S O 4
H N O 3
C H 3 C l
N
N O 2
A lC l3 N
C H 3
N
C O O H
K M n O 4
Z n / H
N
N H 2
B r2
F e B r3 N
C l
N
O C H 3
C H 3 O N a
C H 3 O H
P t
H 2
N
H
piperidine
3-picoline nicotinic acid
3-aminopyridine
Pyridine
N
H
N
N
C
H
3
nicotine
Electrophilic Reactions
Organic Chemistry 3
61. 61
Synthesis of Pyridoxine (Vitamin B6) Using the Guareschi Synthesis
H3C
O O
1 3
H2N C CH2CN
O
+
N
H
O
H3C
OC2H5
CN
EtO
N
H
O
H3C
CN
EtO
O2N
N
H3C
CN
EtO
O2N
Cl
N
H3C
CH2OH
HO
HO
Cl
PCl5
HNO3
H2
N
H3C
CN
EtO
H2N
Cl
Organic Chemistry 3
62. 62
N
N N
N
N
N
pyridazine pyrimidine pyrazine
N
H
N
N
H
2
O N
H
H
N
O
O N
H
H
N
O
O
C
H
3
Cytosine Thymine Uracil
bases in nucleic acids
DNA and RNA
C
O
O
H
C
O
O
H
H
N
O
H
N
N
O
H
N
H
2
N
N
N
O H
N
N H 2
N
N
H O
N
xanthopterin folic acid
cancer chemotherapy vitamin B9
Other Six-Membered Heterocycles
Organic Chemistry 3
63. 63
Other Six-Membered Heterocycles
The pyridine ring can be fused with benzene rings to produce polycyclic
aromatic heterocycles.
N N
Quinoline Isoquinoline
Electrophilic substitution in these amines occurs in the carbocyclic ring.
N
1
2
4
3
5
6 H 2 S O 4
H N O 3
-C O 2
N
K M n O 4
7
8
N
N O 2
N
N O 2
H O O C
H O O C N
H O O C
+
quinolinic acid
5-nitroquinoline
Organic Chemistry 3
65. 65
Five-Membered Heterocycles: Furan, Pyrrole, and
Thiophene
O S
N
H
furan pyrrole thiophene
N
O
N
N
H
N
S
thiazole
oxazole imidazole
Other Five-Membered Heterocycles: Azoles
Organic Chemistry 3
66. 66
N H 2
H N
N
O
O H
N H 2
H N
N
D e c a r b o x y la tio n
histidine histamine
Pyrrole is obtained commercially
by distillation of coal tar or from
furan, ammonia, and a catalyst.
Thiophene is obtained by heating
a mixture of butanes and butenes
with sulfur.
CH O
H O H
H O H
H O H
CH 2O H
O CH O
HCl, Heat
furfural
Synthesis
Organic Chemistry 3
68. 68
O
R1 R2
O
TsOH
O R2
R1
O
R1 R2
O
P2S5
S R2
R1
N
H
R2
R1
General strategies for heterocycle synthesis
1+4 strategy: Paal–Knorr Synthesis
N
H
+
O
R
1 R
2
N
H
2 O
R
3 O
C
2
H
5
O R
3
C
O
O
C
2
H
5
R
1
R
2
Substitutedpyrrole
α-aminoketone α‐ketoester Organic Chemistry 3
70. 70
Difference between five- and six-membered aromatic heterocycles
O O O O O
As might be expected, this enhances their susceptibility to attack by
electrophiles.
O
H
N
O
3
O N
O
2
N
H
B
r
2
O B
r
E
t
h
e
r
S S
CC
H
3
O
H
3
C
C
O
C
l
2-methylthiophene
2-acetyl-5-methylthiophene
Organic Chemistry 3
71. 71
Fused-Ring Five-Membered Heterocycles:
Indoles and Purines
N
H
Tryptamine
Tryptophan
Indole
N
H
N N
N
H
2
N
N
H
O
O
H
N
H
2
H
N
N H
O
N
H
N
H
O
H
N
O
O
N
N
N
N
O
N
N
N
H
2
N
H
N
H
N
N N NH2
NH
O
Guanine
Adenine
Caffeine
Uric acid
Purine
Organic Chemistry 3
72. 72
N
O
F 3 C
O C H 3
N
O
F 3 C
O C H 3
H
N
H
C H 3
P o l y p h o s p h i r i c
a c i d
Bischler Synthesis
NO2
CH3
N
H
O O
OEt
EtO
Base
NO2
O
COOEt
NH2
O
COOEt
CO2Et
+ H2
Reissert Synthesis
Organic Chemistry 3
