PHMD 212 heterocyclics and biomacromoles pdf

Chemistry lecture slides

1. PHMD 212
Heterocyclic Compounds
and
Biomacromolecules

2. Recommended textbooks
1.John McMurry(2008); Organic Chemistry, 7th
Edition.
2.T W Graham Solomons, Craig B Fryhle(2011);
Organic Chemistry, 10thEdition,
3.Paula YurkanisBruice(2007); 5thEdition,
Organic Chemistry; Prentice Hall. ISBN: 0-13-
196316-3
4.L G Wade, Jr. (2003); 5thEdition, Organic
Chemistry; Prentice Hall. ISBN: 0-13-033832-X

3. Heterocyclic
compounds

4. Introduction
•A homocyclic compound comprise of only
carbon atoms in the ring structure.
BenzeneNaphthaleneCyclopentadiene
CyclohexaneCyclohexanol

5. Introduction
•A heterocyclic compound is a compound that
contains a ring made of more than one kind of
atom (carbon and heteroatoms)

6. Introduction
Purine
Piperidine

7. Introduction
Tetrahy-
drofuranTetrahydro-
thiophenePyrrolidinePyrroline
CarbazoleIndoleCarbolineDiazepine

8. Introduction
HistamineAdenineNicotine
AdenosineThiamine (Vit B1)Penicillin G

9. Introduction
Diazepam
Reserpine
Chlorpromazine

10. Introduction
Pyridoxal
phosphate,
a co-enzymeSildenafil (Viagra)

11. Introduction
Heme

12. Introduction

13. Introduction

14. Five-membered rings
•Furan, thiophene and pyrrole do
not undergo the general reactions
associated with dienes.
•Furan, thiophene and pyrrole are
aromatic
FuranThiophenePyrrole

15. Pyrrole
•Pyrroles are components of complex
macrocycles such as the porphyrinogens and
their derivatives including porphyrins of
heme, the chlorins, and chlorophylls.
Names
Preferred IUPAC name
1 H -Pyrrole
[2]
Other names
Azole
Imidole
[1]
Identifiers
CAS Number
109-97-7 ( https://comm
onchemistry.cas.org/de
tail?cas_rn=109-97-7 )
 
3D model
( JSmol )
Interactive image ( http
s://chemapps.stolaf.ed
u/jmol/jmol.php?model
=N1C%3DCC%3DC1 )
Interactive image ( http
s://chemapps.stolaf.ed
u/jmol/jmol.php?model
=%5BnH%5D1cccc1 )
Beilstein
Reference
11 5 9
ChEBI
CHEBI:19203 ( https://
www.ebi.ac.uk/chebi/s
earchId.do?chebiId=19
203 )
 
ChEMBL
ChEMBL16225 ( https://
www.ebi.ac.uk/chembl
db/index.php/compoun
d/inspect/ChEMBL162
25 )
 
ChemSpider
7736 ( https://www.che
mspider.com/Chemica
l-Structure.7736.html )
 
ECHA
InfoCard
100.003.387 ( https://ec
ha.europa.eu/substanc
e-information/-/substan
ceinfo/100.003.387 )
Pyrrole
Structure of Heme B
Pyrrole
Pyrrole is a heterocyclic , aromatic , organic compound , a five-membered ring with the formula
C
4
H
4
NH .
[3]
It is a colorless volatile liquid that darkens readily upon exposure to air.
Substituted derivatives are also called pyrroles, e.g., N -methylpyrrole, C
4
H
4
NCH
3
.
Porphobilinogen , a trisubstituted pyrrole, is the biosynthetic precursor to many natural
products such as heme .
[4]
Pyrroles are components of more complex macrocycles, including the porphyrinogens and
products derived therefrom, including porphyrins of heme , the chlorins , bacteriochlorins, and
chlorophylls .
[5]
Pyrrole is a colorless volatile liquid that darkens readily upon exposure to air, and is usually
purified by distillation immediately before use.
[6]
Pyrrole has a nutty odor. Pyrrole is a 5-
membered aromatic heterocycle, like furan and thiophene . Unlike furan and thiophene, it has a
dipole in which the positive end lies on the side of the heteroatom, with a dipole moment of
1.58  D . In CDCl
3
, it has chemical shifts at 6.68 (H2, H5) and 6.22 (H3, H4). Pyrrole is an
extremely weak base for an amine, with a conjugate acid p K
a
of −3.8. The most
thermodynamically stable pyrrolium cation (C
4
H
6
N
+
) is formed by protonation at the 2
position. Substitution of pyrrole with alkyl substituents provides a more basic molecule—for
example, tetramethylpyrrole has a conjugate acid p K
a
of +3.7. Pyrrole is also weakly acidic at
the N–H position, with a p K
a
of 16.5. As a hydrogen bonding Lewis acid it is classified as a hard
acid and the ECW model lists its acid parameters as E
A
= 1.38 and C
A
= 0.68.
Pyrrole has aromatic character because the lone pairs of electrons on the nitrogen atom is
partially delocalized into the ring, creating a 4 n  + 2 aromatic system (see Hückel's rule ). In
terms of its aromaticity, pyrrole's is modest relative to benzene but comparable to related
heterocycles thiophene and furan . The resonance energies of benzene, pyrrole, thiophene , and
furan are, respectively, 152, 88, 121, and 67 kJ/mol (36, 21, 29, and 16 kcal/mol).
[7]
The
molecule is flat.
Pyrrole was first detected by F. F. Runge in 1834, as a constituent of coal tar .
[8]
In 1857, it was
isolated from the pyrolysate of bone . Its name comes from the Greek pyrrhos ( πυρρός ,
"reddish, fiery"), from the reaction used to detect it—the red color that it imparts to wood when
moistened with hydrochloric acid .
[9]
Pyrrole itself is not naturally occurring, but many of its derivatives
are found in a variety of cofactors and natural products . Common
naturally produced molecules containing pyrroles include vitamin
B
12
, bile pigments like bilirubin and biliverdin , and the porphyrins of
heme , chlorophyll , chlorins , bacteriochlorins , and porphyrinogens.
[5]
Other pyrrole-containing secondary metabolites include PQQ,
makaluvamine M, ryanodine, rhazinilam, lamellarin, prodigiosin,
myrmicarin, and sceptrin. The syntheses of pyrrole-containing
haemin, synthesized by Hans Fischer was recognized by the Nobel
Prize.
Pyrrole is a constituent of tobacco smoke and may contribute to its
toxic effects.
[10]
Properties, structure, bonding
History
Occurrence in nature
Synthesis
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16. Pyrrole
•Pyrrole itself is not naturally occurring, but
many of its derivatives are found in a variety
of cofactors and natural products.
•Common naturally produced molecules
containing pyrroles include vitamin B12, bile
pigments like bilirubin and biliverdin, and the
porphyrins of heme, chlorophyll, chlorins,
bacteriochlorins, and porphyrinogens

17. Pyrrole
•Other pyrrole-containing secondary
metabolites include PQQ, makaluvamineM,
ryanodine, rhazinilam, lamellarin, prodigiosin,
myrmicarin, and sceptrin.

18. Pyrrole
•Pyrrole is a five membered aromatic
compound
•It has a dipole in which the positive end lies
on the side of the heteroatom
•Pyrrole is an extremely weak base for an
amine, with a conjugate acid pKaof −3.8.

19. Pyrrole
•The most thermodynamically stable pyrrolium
cation (C4H6N+) is formed by protonation at
the 2 position.
•Substitution of pyrrole with alkyl substituents
provides a more basic molecule—for example,
tetramethylpyrrolehas a conjugate acid pKa
of +3.7.
•Pyrrole is also weakly acidic at the N–H
position, with a pKaof 16.5.

20. Pyrrole
•Pyrrole has aromatic character because the
lone pairs of electrons on the nitrogen atom is
partially delocalized into the ring, creating a
4n + 2 aromatic system
•Pyrrole is modestly compared to benzene but
comparable to thiophene and furan.
•The resonance energies of benzene, pyrrole,
thiophene, and furan are, respectively, 152,
88, 121, and 67 kJ/mol.

21. Pyrrole Synthesis
•Pyrrole is prepared industrially by treatment
of furan with ammonia in the presence of
solid acid catalysts, like SiO2and Al2O3

22. Pyrrole Synthesis
•Catalytic dehydrogenation of pyrrolidine.
•Passing a mixture of acetylene and ammonia
through a red hot tube

23. Pyrrole Synthesis
•Heating succinimide with zinc dust
•Warming succinic dialdehyde with ammonia

24. Pyrrole Synthesis

25. Hantzschpyrrole synthesis
•The Hantzschpyrrole synthesis is the reaction
of β-ketoesters(1) with ammonia (or primary
amines) and α-haloketones (2) to give
substituted pyrroles (3)
[ show ]
[ show ]
EC Number
203-724-7
Gmelin
Reference
1705
PubChem
CID
8027 ( https://pubche
m.ncbi.nlm.nih.gov/co
mpound/8027 )
RT E C S
number
UX9275000
UNII
86S1ZD6L2C ( https://p
recision.fda.gov/uniise
arch/srs/unii/86S1ZD6
L2C )
 
UN number 1992, 1993
CompTox
Dashboard
( EPA )
DTXSID5021910 ( http
s://comptox.epa.gov/da
shboard/chemical/detai
ls/DTXSID5021910 )
InChI
InChI=1S/C4H5N/c1-2-4-5-3-1/h1-5H
 
Key: KAESVJOAVNADME-UHFFFAOY
SA-N
 
InChI=1/C4H5N/c1-2-4-5-3-1/h1-5H
SMILES
N1C=CC=C1
[nH]1cccc1
Properties
Chemical
formula
C
4
H
5
N
Molar mass 67.091  g·mol
−1
Density 0.967 g cm
−3
Melting point −23 °C (−9 °F; 250 K)
Boiling point 129 to 131 °C (264 to
268 °F; 402 to 404 K)
Va p o r
pressure
7 mmHg at 23 °C
Acidity (p K
a
) 17.5 (for the N−H
proton)
Basicity (p K
b
) 13.6 (p K
a
0.4 for C.A. )
Magnetic
susceptibility
(χ)
−47.6 × 10
−6
 cm
3
 mol
−1
Vi s c o s i t y 0.001225 Pa s
Thermochemistry
Heat capacity
( C )
1.903 J K
−1
 mol
−1
Std enthalpy
of
formation
(Δ
f
H
!
298
)
108.2 kJ mol
−1
(gas)
Std enthalpy
of
combustion
(Δ
c
H
!
298
)
2242 kJ mol
−1
Hazards
Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid
acid catalysts , like SiO
2
and Al
2
O
3
.
[9]
Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.
Several syntheses of the pyrrole ring have been described.
[11]
Three routes dominate,
[12]
but
many other methods exist.
The Hantzsch pyrrole synthesis is the reaction of β-ketoesters ( 1 ) with ammonia (or primary
amines) and α-haloketones ( 2 ) to give substituted pyrroles ( 3 ).
[13] [14]
The Knorr pyrrole synthesis involves the reaction of an α-amino ketone or an α-amino-β-
ketoester with an activated methylene compound.
[15] [16] [17]
The method involves the reaction of
an α- amino ketone ( 1 ) and a compound containing a methylene group α to (bonded to the next
carbon to) a carbonyl group ( 2 ).
[18]
In the Paal–Knorr pyrrole synthesis, a 1,4-dicarbonyl compound reacts with ammonia or a
primary amine to form a substituted pyrrole.
[19] [20]
Van Leusen reaction pyrroles are produced by reaction of tosylmethyl isocyanide (TosMIC)
with an enone in the presence of base, in a Michael addition . A 5- endo cyclization then forms
the 5-membered ring, which reacts to eliminate the tosyl group. The last step is
tautomerization to the pyrrole.
Hantzsch pyrrole synthesis
Knorr pyrrole synthesis
Paal–Knorr pyrrole synthesis
Other methods
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26. Knorr Pyrrole Synthesis
•The Knorr pyrrole synthesis involve the rection
of α-aminoketone (1) and a compound
containing a methylene group α to (bonded to
the next carbon to) a carbonyl group (2)
[ show ]
[ show ]
EC Number
203-724-7
Gmelin
Reference
1705
PubChem
CID
8027 ( https://pubche
m.ncbi.nlm.nih.gov/co
mpound/8027 )
RT E C S
number
UX9275000
UNII
86S1ZD6L2C ( https://p
recision.fda.gov/uniise
arch/srs/unii/86S1ZD6
L2C )
 
UN number 1992, 1993
CompTox
Dashboard
( EPA )
DTXSID5021910 ( http
s://comptox.epa.gov/da
shboard/chemical/detai
ls/DTXSID5021910 )
InChI
InChI=1S/C4H5N/c1-2-4-5-3-1/h1-5H
 
Key: KAESVJOAVNADME-UHFFFAOY
SA-N
 
InChI=1/C4H5N/c1-2-4-5-3-1/h1-5H
SMILES
N1C=CC=C1
[nH]1cccc1
Properties
Chemical
formula
C
4
H
5
N
Molar mass 67.091  g·mol
−1
Density 0.967 g cm
−3
Melting point −23 °C (−9 °F; 250 K)
Boiling point 129 to 131 °C (264 to
268 °F; 402 to 404 K)
Va p o r
pressure
7 mmHg at 23 °C
Acidity (p K
a
) 17.5 (for the N−H
proton)
Basicity (p K
b
) 13.6 (p K
a
0.4 for C.A. )
Magnetic
susceptibility
(χ)
−47.6 × 10
−6
 cm
3
 mol
−1
Vi s c o s i t y 0.001225 Pa s
Thermochemistry
Heat capacity
( C )
1.903 J K
−1
 mol
−1
Std enthalpy
of
formation
(Δ
f
H
!
298
)
108.2 kJ mol
−1
(gas)
Std enthalpy
of
combustion
(Δ
c
H
!
298
)
2242 kJ mol
−1
Hazards
Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid
acid catalysts , like SiO
2
and Al
2
O
3
.
[9]
Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.
Several syntheses of the pyrrole ring have been described.
[11]
Three routes dominate,
[12]
but
many other methods exist.
The Hantzsch pyrrole synthesis is the reaction of β-ketoesters ( 1 ) with ammonia (or primary
amines) and α-haloketones ( 2 ) to give substituted pyrroles ( 3 ).
[13] [14]
The Knorr pyrrole synthesis involves the reaction of an α-amino ketone or an α-amino-β-
ketoester with an activated methylene compound.
[15] [16] [17]
The method involves the reaction of
an α- amino ketone ( 1 ) and a compound containing a methylene group α to (bonded to the next
carbon to) a carbonyl group ( 2 ).
[18]
In the Paal–Knorr pyrrole synthesis, a 1,4-dicarbonyl compound reacts with ammonia or a
primary amine to form a substituted pyrrole.
[19] [20]
Van Leusen reaction pyrroles are produced by reaction of tosylmethyl isocyanide (TosMIC)
with an enone in the presence of base, in a Michael addition . A 5- endo cyclization then forms
the 5-membered ring, which reacts to eliminate the tosyl group. The last step is
tautomerization to the pyrrole.
Hantzsch pyrrole synthesis
Knorr pyrrole synthesis
Paal–Knorr pyrrole synthesis
Other methods
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27. Paal-Knorr Pyrrole Synthesis
•In the Paal–Knorr pyrrole synthesis, a 1,4-
dicarbonyl compound reacts with ammonia or
a primary amine to form a substituted pyrrole
[ show ]
[ show ]
EC Number
203-724-7
Gmelin
Reference
1705
PubChem
CID
8027 ( https://pubche
m.ncbi.nlm.nih.gov/co
mpound/8027 )
RT E C S
number
UX9275000
UNII
86S1ZD6L2C ( https://p
recision.fda.gov/uniise
arch/srs/unii/86S1ZD6
L2C )
 
UN number 1992, 1993
CompTox
Dashboard
( EPA )
DTXSID5021910 ( http
s://comptox.epa.gov/da
shboard/chemical/detai
ls/DTXSID5021910 )
InChI
InChI=1S/C4H5N/c1-2-4-5-3-1/h1-5H
 
Key: KAESVJOAVNADME-UHFFFAOY
SA-N
 
InChI=1/C4H5N/c1-2-4-5-3-1/h1-5H
SMILES
N1C=CC=C1
[nH]1cccc1
Properties
Chemical
formula
C
4
H
5
N
Molar mass 67.091  g·mol
−1
Density 0.967 g cm
−3
Melting point −23 °C (−9 °F; 250 K)
Boiling point 129 to 131 °C (264 to
268 °F; 402 to 404 K)
Va p o r
pressure
7 mmHg at 23 °C
Acidity (p K
a
) 17.5 (for the N−H
proton)
Basicity (p K
b
) 13.6 (p K
a
0.4 for C.A. )
Magnetic
susceptibility
(χ)
−47.6 × 10
−6
 cm
3
 mol
−1
Vi s c o s i t y 0.001225 Pa s
Thermochemistry
Heat capacity
( C )
1.903 J K
−1
 mol
−1
Std enthalpy
of
formation
(Δ
f
H
!
298
)
108.2 kJ mol
−1
(gas)
Std enthalpy
of
combustion
(Δ
c
H
!
298
)
2242 kJ mol
−1
Hazards
Pyrrole is prepared industrially by treatment of furan with ammonia in the presence of solid
acid catalysts , like SiO
2
and Al
2
O
3
.
[9]
Pyrrole can also be formed by catalytic dehydrogenation of pyrrolidine.
Several syntheses of the pyrrole ring have been described.
[11]
Three routes dominate,
[12]
but
many other methods exist.
The Hantzsch pyrrole synthesis is the reaction of β-ketoesters ( 1 ) with ammonia (or primary
amines) and α-haloketones ( 2 ) to give substituted pyrroles ( 3 ).
[13] [14]
The Knorr pyrrole synthesis involves the reaction of an α-amino ketone or an α-amino-β-
ketoester with an activated methylene compound.
[15] [16] [17]
The method involves the reaction of
an α- amino ketone ( 1 ) and a compound containing a methylene group α to (bonded to the next
carbon to) a carbonyl group ( 2 ).
[18]
In the Paal–Knorr pyrrole synthesis, a 1,4-dicarbonyl compound reacts with ammonia or a
primary amine to form a substituted pyrrole.
[19] [20]
Van Leusen reaction pyrroles are produced by reaction of tosylmethyl isocyanide (TosMIC)
with an enone in the presence of base, in a Michael addition . A 5- endo cyclization then forms
the 5-membered ring, which reacts to eliminate the tosyl group. The last step is
tautomerization to the pyrrole.
Hantzsch pyrrole synthesis
Knorr pyrrole synthesis
Paal–Knorr pyrrole synthesis
Other methods
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28. Pyrrole reactions and reactivity
•Due to its aromatic character, pyrrole is
difficult to hydrogenate
–does not easily react as a diene in Diels–Alder
reactions,
–does not undergo usual olefin reactions.
•Its reactivity is similar to that of benzene and
aniline
–it is easy to alkylate and acylate.

29. Pyrrole reactions and reactivity
•Pyrrole generally react with electrophiles
preferentially at either of the position 2
followed by 3
Due to its aromatic character , pyrrole is difficult to hydrogenate , does not easily react as a diene in Diels–Alder reactions, and does
not undergo usual olefin reactions. Its reactivity is similar to that of benzene and aniline , in that it is easy to alkylate and acylate.
Under acidic conditions, pyrroles oxidize easily to polypyrrole ,
[30]
and thus many electrophilic reagents that are used in benzene
chemistry are not applicable to pyrroles. In contrast, substituted pyrroles (including protected pyrroles) have been used in a broad
range of transformations.
[11]
Pyrroles generally react with electrophiles at the α position (C2 or C5), due to the highest degree of stability of the protonated
intermediate.
Pyrroles react easily with nitrating (e.g. HNO
3
/ Ac
2
O ), sulfonating ( Py·SO
3
), and halogenating (e.g. NCS , NBS , Br
2
, SO
2
Cl
2
, and KI /
H
2
O
2
) agents.
[31]
Halogenation generally provides polyhalogenated pyrroles, but monohalogenation can be performed. As is typical
for electrophilic additions to pyrroles, halogenation generally occurs at the 2-position, but can also occur at the 3-position by silation
of the nitrogen. This is a useful method for further functionalization of the generally less reactive 3-position.
Acylation generally occurs at the 2-position, through the use of various methods. Acylation with acid anhydrides and acid chlorides
can occur with or without a catalyst.
[32]
2-Acylpyrroles are also obtained from reaction with nitriles, by the Houben–Hoesch reaction .
Pyrrole aldehydes can be formed by a Vilsmeier–Haack reaction .
[33]
The NH proton in pyrroles is moderately acidic with a p K
a
of 17.5.
[34]
Pyrrole can be deprotonated with strong bases such as
butyllithium and sodium hydride .
[35]
The resulting alkali pyrrolide is nucleophilic . Treating this conjugate base with an electrophile
such as iodomethane gives N -methylpyrrole.
N -Metalated pyrrole can react with electrophiles at the N or C positions, depending on the coordinating metal. More ionic nitrogen–
metal bonds (such as with lithium, sodium, and potassium) and more solvating solvents lead to N -alkylation. Nitrophilic metals, such
as MgX, lead to alkylation at C (mainly C2), due to a higher degree of coordination to the nitrogen atom. In the cases of N - substituted
pyrroles, metalation of the carbons is more facile. Alkyl groups can be introduced as electrophiles, or by cross-coupling reactions.
Reactions and reactivity
Reaction of pyrrole with electrophiles
Acylation
Reaction of deprotonated pyrrole
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•Pyrrole undergoes nitration, sulphonation,
halogenation, acylation.

30. Reactions of pyrrole
•Nitration can be done with cold nitric acid and
acetic anydride
•Sulphonationis achieved with SO3in pyridine
at 100 oC

31. Halogenation of pyrrole
•Halogenation generally leads to
polysubstitution

32. Halogenation of pyrrole

33. Formylation of pyrrole
•Gattermann reaction
AlCl3
2-pyrrolecarboxaldehyde
•Vilsmeier reaction

34. Formylation of pyrrole
•Reimer-Tiemannreaction

35. Acetylation of pyrrole

36. Alkylation of pyrrole

37. Coupling reaction of pyrrole

38. Carboxylation of pyrrole
Kolbe Schmitt reaction

39. Carboxylation of pyrrole

40. Oxidation and Reduction of pyrrole

41. Mannichreaction of pyrrole

42. Ring expansion of pyrrole

43. Ring opening of pyrrole
succindialdoxime

44. Reaction of pyrrole with RMgX
•Pyrrole reacts with Grignard reagents to form
hydrocarbon and N-pyrrole magnesium halide

45. Acidity and basicity

46. Substitution at C3 can be achieved through the use of N -substituted 3-bromopyrrole, which can be synthesized by bromination of N -
silylpyrrole with NBS .
Pyrroles can undergo reductions to pyrrolidines and to pyrrolines .
[36]
For example, Birch reduction of pyrrole esters and amides
produced pyrrolines, with the regioselectivity depending on the position of the electron-withdrawing group.
Pyrroles with N -substitution can undergo cycloaddition reactions such as [4+2]-, [2+2]-, and [2+1]-cyclizations. Diels-Alder
cyclizations can occur with the pyrrole acting as a diene, especially in the presence of an electron-withdrawing group on the nitrogen.
Vinylpyrroles can also act as dienes.
Pyrroles can react with carbenes , such as dichlorocarbene , in a [2+1]-cycloaddition. With dichlorocarbene , a dichlorocyclopropane
intermediate is formed, which breaks down to form 3-chloropyridine (the Ciamician–Dennstedt rearrangement).
[37] [38] [39]
Polypyrrole is of some commercial value. N -Methylpyrrole is a precursor to N -methylpyrrolecarboxylic acid, a building-block in
pharmaceutical chemistry.
[9]
Pyrroles are also found in several drugs, including atorvastatin , ketorolac , and sunitinib . Pyrroles are
used as lightfast red, scarlet, and carmine pigments.
[40] [41]
Structural analogs of pyrrole include:
▪ Pyrroline , a partially saturated analog with one double bond
▪ Pyrrolidine , the saturated hydrogenated analog
Derivatives of pyrrole include indole , a derivative with a fused benzene ring.
▪ Simple aromatic rings
▪ Tetrapyrrole
Reductions
Cyclization reactions
Commercial uses
Analogs and derivatives
See also
Pyrrole - Wikipedia file:///Users/drmichaellartey/Desktop/Pyrrole%20-%20Wikipedia.html
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47. Medicinal uses of pyrroles
•Atorvastatin to lower lipid and reduce the risk
of cardiovascular diseases

48. Medicinal uses of pyrroles
•Tolmetin, an NSAID for treating osteoarthritis

49. Furan synthesis
•From carbohydrates

50. Furan synthesis
•From mucicacid

51. Furan synthesis
•Paal Knorr Synthesis

52. Furan synthesis
•Feist-Benarysynthesis

53. Reactions of furan
•Furan undergoes electrophilic substitution
mainly at position 2
•Substitution occurs at position 3 only when
positions 2 and 5 are occupied.

54. Reactions of furan
•Nitration

55. Reactions of furan
•Sulphonation
•Reaction with diazonium salts (Gomberg
reaction)

56. Reactions of furan
•Acylation

57. Reactions of furan
•Formylation
Gattermann
Vilsmeier

58. Reactions of furan
•Diels Alder reaction

59. Reactions of furan
•Lithiation

60. Reactions of furan
•Oxidation

61. Reactions of furan
•Reduction

62. Reactions of furan
•Alkylation
Alkylation can also be achieved via lithiation
followed by treatment with alkyl halide

63. Reactions of furan
•Halogenation
+ Polymer

64. Reactions of furan
Halogenation

65. Reactions of furan
•Nucleophilic substitution

66. Reactions of furan
•Ring opening

67. Reactions of furan
•Coupling with diazonium salts

68. Medicinal uses of furan
Ranitidine
Furosemide

69. Thiophene synthesis
Paal Knorr synthesis:
Reaction of butane with sulphur

70. Thiophene synthesis
SimmonSmith:

71. Thiophene synthesis
Hinsbergsynthesis: condensation of 1,2-
dicarbonyl compounds with diethyl
thiodiacetatein the presence of strong base

72. Thiophene synthesis
From sodium succinate
GewaldAminothiophenesynthesis

73. Thiophene synthesis
From acetylene
Distilling furoic acid with BaS

74. Thiophene reactivity
•Like many aromatic compounds, thiophene
undergoes electrophilic substitution.
•They are more reactive than benzene
–They are as reactive as the most reactive
benzene derivatives e.gphenols and amines
•Reaction occurs predominantly in position 2

79. Thiophene reactivity
Chloromethylation

80. Thiophene reactivity
Vilsmeierformylation

81. Thiophene reactivity
Reduction

82. Saturated five-membered rings
•Since thiophenepoisons most catalysts,
tetrahydrothiopheneis made from open chain
compounds
•The saturated compounds are not aromatic
and exhibit the chemical characteristics of
their open chain analogs

83. Pyridine
•Pyridine is flat with bond angles of 120o
•The four C-C bonds are of the same length
•The two N-C bonds are of the same length
•Pyridine resists addition and undergoes
electrophilic substitution
•Pyridine is aromatic (cyclic, conjugated and
contains (4n + 2) pi-electrons
•The heat of combustion indicates a resonance
energy of 23 kcal/mol

84. Synthesis of pyridine
Hanztschsynthesis

85. Synthesis of pyridine
Hanztschsynthesis
2,3-Dichloro-5,6-dicyano-
1,4-benzoquinone

86. Synthesis of pyridine
Guareschisynthesis
Synthesis from acetylene

87. Synthesis of pyridine
•Oxidation of picoline (found in coal tar) yields
pyridinecarboxylicacids

88. Synthesis of pyridine
Chichibabinpyridine synthesis
Synthesis from pyrrole

89. Synthesis of pyridine
•Synthesis from piperidine

90. Reactions of pyridine
•Pyridine undergoes
–Electrophilic and
–nucleophilic substitution.
•Pyridine acts as a
–Base
–nucleophile

91. Electrophilic substitution
•Pyridine’s reactivity towards electrophilic
substitution is similar to a benzene derivative.
•It undergoes nitration, sulphonationand
halogenation only under vigorous conditions.
•Electrophilic substitutions occur mainly at
the 3-position.
•Pyridine does not undergo Friedel-Crafts
reactions.

92. Electrophilic substitution

93. Nucleophilic substitution
•Nucleophilic substitution takes place in
position 2 (and 4 if position 2 is occupied)
Chichibabinreaction
Alkylation

94. Nucleophilic substitution
Hydroxylation

95. Basicity and nucleophilicity of pyridine
•Pyridine is a base with a Kb= 2.3 x 10-9
–More basic than pyrrole (Kb~2.5 x 10-14) but less
basic than amines (Kb~10-4)
•Pyridine has nucleophilic properties
–Reacts with R-X to form pyridiniumsalts

96. Basicity and nucleophilicity of pyridine
N-acetyl pyridinium chloride

97. Reduction

98. Oxidation of pyridine
•N-oxidation is possible

99. Oxidation of pyridine
•N-oxidation is possible

100. Reactions of pyridine N-oxide

101. Reactionsofpyridine N-oxide