1. The document is from the Department of Pharmacy at the College of Medical Sciences in Yemen and discusses organic chemistry topics related to amines. 2. Key topics covered include the nomenclature, structure, properties, synthesis, and reactions of amines. Common amine synthesis methods like reduction of nitro compounds and reductive amination are described. 3. The document also discusses stereochemistry and isomerism related to amines, including chiral and achiral molecules, enantiomers, and diastereomers.

1. ‫اليمنية‬ ‫الجمهورية‬
‫وزارة‬
‫التعليم‬
‫والبحث‬ ‫العالي‬
‫العلم‬
‫ي‬
‫الطبية‬ ‫العلوم‬ ‫كلية‬
‫الصيدلة‬ ‫قسم‬
Republic of Yemen
Ministry of Higher Education
& Scientific Research
College of medical sciences
Department of pharmacy
Organic Chemistry 3
Dr. Arwa Al-Shargabi

2. Introduction
N
H
2
H
O
H
O
H
O
O
H
N
H
H
O
N
H
2
H
N
O
O
H
Dopamine
Epinephrine
L-tryptophan
N
N
Nicotine
Tobacco
Amino acid
Neurotransmitter
Adrenal hormone
N
H O
H O O H
Pyridoxine
Vitamin B6
Cocaine
N
O O
O
C
O
Coca leaves
Organic Chemistry 3 2
Amines

3. N H 2
C H 3
3-methyl-1-butanamine 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
Organic Chemistry 3 3

4. 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
Organic Chemistry 3 4

5. 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
Organic Chemistry 3 5

6. 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
Organic Chemistry 3 6

7. 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
Organic Chemistry 3 7

8. Reductive amination
Organic Chemistry 3 8
+
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

9. Organic Chemistry 3 9
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

10. Reduction of halide with ammonia or amines
Benzylchloride Benzylamine
Organic Chemistry 3 10
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

11. Organic Chemistry 3 11
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

12. Organic Chemistry 3 12
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

13. Organic Chemistry 3 13
 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

14. Organic Chemistry 3 14
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

15. Organic Chemistry 3 15
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

16. 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
Organic Chemistry 3 16

17. 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
Organic Chemistry 3 17

18. Organic Chemistry 3 18
 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

19. Organic Chemistry 3 19
Stereochemistry
Is the three dimensional of molecule
Hands are mirror image but not identical
O
H
O
O
H
H
O H
H
O H
C H 2O H
H
O
H
O
H
H
O H
H
O H
C H 2O H
H
O
H
O
H
H
O H
H
O H
C H 2O H
H
Cellulose Amylose
α
β
O
H
O O
H
H
O
H
H
O
H
C
H
2
O
H
H
O
H
O
H
H
O
H
H
O
H
C
H
2
O
H
H
O
H
O
H
H
O
H
H
O
H
C
H
2
O
H
H

20. Organic Chemistry 3 20
Isomers
H C C
C
H
3
H H
H
C
H
3
H
C
C
H
C
H
3
H
H
C
H
3
trans cis
 Constitutional isomer: have the same chemical formula but differ on the way of
atoms connected together.
 Stereochemistry: differ only on the oriented in space.
H
3
C
O
C
H
3 H
3
C
C
H
2
O
H
Ether Alcohol

21. Organic Chemistry 3 21
Chiral and Achiral molecules
Hands are mirror image but not identical
Chiral is the atom that attached to different group, not superimposed
on it mirror image (not plan symmetry and hence it called enantiomer)
Achiral is superimposed on it mirror image (plan symmetry)
CH
F
C
l
O
H
CB
r
H
H
O
H
Chiral and not superimposed Achiral and superimposed
CH3
H
Enantiomers

22. Organic Chemistry 3 22
Locate the chiral centre, cis and trans, symmetric and non symmetric molecule
O
H H
CC
F
C
l
C
H
3C
H
3
F
C
l
C
F
C
H
3
C
H
2
O
H
C OH
H
C H
HO
C OH
H
C OH
H
CH2OH
C
O H
H
2
N C
H
C
O
O
H
H
Br
F
Glycine Glucose
C
H
3
Thalidomide
N
H
N
O O
O
O
H

23. Organic Chemistry 3 23
Chiral centres: R and S isomers
R: clockwise
The atom with highest atomic number gets highest priority
1
2
3
4
C B r
C l
F
H
S: counter clockwise
C CH2CH3
OH
H
CH3
1
2
3
4
1
2
3
4
C B r
H
F
C l
Racemic mixture: When R equal to S
(optically inactive)
C H
OH
H3CH2C
CH3
1
2
3
4

24. Organic Chemistry 3 24
R: clockwise
C COOH
OH
CH3
H C CH2Br
OH
CH2Cl
H3C
Label the following compound as S and R Enantiomers: 2n n= chiral centres
Enantiomers
C
C
H
3
C
C
H
2
C
H
3
B
r B
r
H
H
Enantiomers
Rotation
1 2
C C
H
3
C
H
2
C C
H
3
B
r B
r
H H
C C
H
3
O
H
C
H
C
H
2
C
H
3
1
2
3
4

25. Organic Chemistry 3 25
C C
H3C CH2CH3
Br Br
H H
C
C
H
3
C
C
H
2
C
H
3
B
r B
r
H
H
Enantiomers
Diastereomers: NOT MIRROR IMAGE OF EACH OTHER
1 2
1 3 4
Diastereomers
C C
H
3
C
H
2
C C
H
3
B
r B
r
H H
Enantiomers
C
C
H
3
C
C
H
2
C
H
3
H
B
r
B
rH
CC
H
3
C
H
2
C C
H
3
B
r H
H B
r

26. Organic Chemistry 3 26
Draw the enantiomer and diasteromer for the following compound
CC
H
3
C C
O
O
H
H
O O
H
H H
Enantiomers
Enantiomers
Diastereomers
C C
H
O
O
C C
H
3
H H
H
O O
H
C
C
H
3
C C
O
O
H
H H
H
O O
H
C C
H3C COOH
HO H
H OH
C C
HOOC CH3
H OH
HO H

27. Organic Chemistry 3 27
R and S Assignment in compound with two or more chiral centres
2S, 3R,-2,3-dibromopentane
R: clockwise
S: counter clockwise
C C
H
O
O
C C
H
3
H O
H
H
O H
(2S,3R)-2,3-dihydroxybutanoic acid
Draw the following compounds:
1- (2R,3S)-2,3-hexanediol and (2R,3R)-2,3-hexanediol
2- (2R,3R)-2,3-hexanediol and (2S,3S)-2,3-hexanediol
1
2
3
4
C C
C
H
3 B
r
1
2
3
4
B
r
H H
C
H
2
C
H
3

28.  Defines as more complex ring systems having two or more fused benzene
rings.
 they have nonsystematic names and illogical numbering systems.
 In anthracene the rings are connected β in a linear manner, whereas in
phenanthrene they are connected angularly.
Naphthalene Anthracene Phenanthrene
Benzene
β
α
80 ºC 216 ºC 101 ºC
Polynuclear Aromatic Compounds
Organic Chemistry 3 28

29. 1-methylnaphthalene 2-methylnaphthalene 1-methylanthracene
9-methylphenanthrene
 How many structurally different monomethyl derivatives are possible of the
naphthalene?
1-naphthoic acid
Nomenclature of polynuclear aromatic compounds
10-methylphenanthren-9-amine
Organic Chemistry 3 29

30.  the reactivity in substitution and addition reactions increase from benzene to
anthracene.
Physical and chemical properties of Napthalene
 Substitution usually occurs more readily at the 1 position than at the 2 position
because the intermediate for 1-substitution is more stable than that for 2-
substitution
Organic Chemistry 3 30

31. Halogenation
Nitration
Substitution reaction
Organic Chemistry 3 31

32. Sulphonation
Sometimes, small changes in the
reagents and conditions change
the pattern of orientation.
Organic Chemistry 3 32

33. Friedel craft acylation
Organic Chemistry 3 33

34. Addition reactions
Naphthalene can be reduced more easily than benzene. With sodium in alcohol.
Reduction
Organic Chemistry 3 34

35. Naphthalene can be similarly oxidized to 1,2-benzenedioic (phthalic) anhydride
naphthalene-1,4-dione
Oxidation
Organic Chemistry 3 35

36.  When a donating group (X, OH, CH3, NHR,) located at position 1,
hence the second substitution will occur at the same ring at position 4 or
maybe 2.
Orientation of substitution in Naphthalene and its derivatives
Organic Chemistry 3 36

37. 4-phenylazo1-naphthol
 When a donating group located at position 2, hence the second substitution will
occur at the same ring at position 1
Organic Chemistry 3 37

38. Reduction
Tetrahydronaphthol
 When a withdrawing group located at position 1 or 2, hence the second
substitution will occur at the other ring at positions 5, 8
Organic Chemistry 3 38

39. Predict the orientation in the following reactions:
a. I-methylnaphthalene + Br2,
b. 2-naphthalenecarboxylic acid + HNO3
C. 2-methylnaphthalene + HNO3
Show how to accomplish the synthesis of the following:
1- Naphthalene to aminonapthalene.
2- Naphthalene to 1-chloronaphthalene -2-carboxilic acid.
Organic Chemistry 3 39

40. Organic Chemistry 3 40
Nomenclature
 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.
 Hetero-atom is to be counted as 1 or as low as possible.
 Substituents are numbered as low as possible.
 Heterocycles can be divided into two subgroups: nonaromatic and aromatic.
 Hantzsch-Widman System of systematic name of heterocyclic compounds.
Atom
O oxa
S thia
N aza
Priority decreases
Prefix
Old Soldiers Never Cry

41. Organic Chemistry 3 41
Hantzsch-Widman rules
N-present
Ring size N-absent
Unsat
irene
ete
ole
in
epin
sat
irane
etane
olane
ane
epane
Unsat
irine
ete etidine
ole
ine
epine
sat
iridine
olidine
a
a

42. Organic Chemistry 3 42
1H-Azole
pyrrole
1H-Azinane
piperidine
[1,3]-diazine
pyrimidine
1,2,5-Oxadiazole
1,2-oxazetidine
5-Amino-4-bromoisoxazole
2,3,4,5-Tetrahydroazine 1,2-Dihydroazine

43. Organic Chemistry 3 43
Explain how can you name the following heterocycles.
O S N N
N
O
N S
Br

44. 44
Organic Chemistry 3
Five-Membered Heterocycles: Furan, Pyrrole, and
Thiophene
O S
N
H
furan pyrrole thiophene
Other Five-Membered Heterocycles: Azoles
N
O
N
N
H
N
S
Thiazole
Oxazole Imidazole Pyrazole

45. Organic Chemistry 3 45
Synthesis
Furan
Pyrrole
Thiophene

46. Organic Chemistry 3 46

47. Organic Chemistry 3 47
Reactivity of Five-Membered Heterocycles: Furan, Pyrrole, and
Thiophene
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

48. 48
Organic Chemistry 3
Pyrazole
Synthesis
Triazoles
Isoxazoles
hydrazine
hydroxylamine

49. 49
Organic Chemistry 3
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
Pyridine

50. Organic Chemistry 3 50
 Electrophilic substitution occur at carbons 3,5.
 Nucleophilic substitution occur at carbons 2,4,6.
Substitution in Pyridine
pyridine is miscible with most organic
solvents and also completely miscible
with water! polar !
weakly basic
React with strong acids

51. 51
Organic Chemistry 3
R
2
R
1
OO
1 3 +
H
2
N
C
N
N
H
X
R
1
R
2
N
H
2
X
O
R
1
O
R
N
H
3
N
R
R
1
Synthesis
Pyridine
Pyrimidine
Pyridazine

52. 52
Other Six-Membered Heterocycles Containing Oxygen
Organic Chemistry 3
3,4-dihydropyrans
2H-pyran-2-ones-5-
carboxilic acid
Pyran and pyron

53. Organic Chemistry 3 53
Antimicrobial drug
Antifungal agent
ciclopirox

54. Organic Chemistry 3 54
Antiinflammatory agent
prodolic acid

55. 55
Organic Chemistry 3
Bicyclic rings contanining one or more
heteroatoms
N
H
Flavone
Indole
N
H
N N
N
N H
O
N
H
N
H
O
H
N
O
Carbazole Uric acid
Purine
N N
Quinoline Isoquinoline
Chromen-2-one
Acridine

56. Organic Chemistry 3 56
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
Quinterenol,
beta adrenergic
Stimulant

57. Organic Chemistry 3 57
Clamoxyquine is an
antidiarrheal drug
Antiviral agent
memotine
Quinoline
Isoquinoline

58. Organic Chemistry 3 58
Fibrinolytic agent, bisobrin, is the
breakdown (lysis) of blood clots
formed in blood vessels.
Isoquinoline

59. Organic Chemistry 3 59
Indoramin, antihypertensive
Indole

60. Organic Chemistry 3 60
Muscle relaxant rolodine
Purine

61. Organic Chemistry 3 61
Acridone anticancer, antimicrobial,
antiviral, antimalarial and anti-
inflammatory activities.
Amustaline is a quinacrine mustard
compound with potential antineoplastic
activity.
Acridine
Synthesis

62. Organic Chemistry 3 62
Carbazole

63. Organic Chemistry 3 63
Synthesis
Hepatitis C virus (HCV)