Unit 3 furan & thiophene

Pharmaceutical organic Chemistry 3 B.Pharm IV SEM

1. UNIT 3
SYNTHESIS REACTIONS &
MEDICINAL USES OF FURAN &
THIOPHENE
Presented by
P.SOWMIYA
Assistant Professor
Dept. of Pharmaceutical Chemistry
SVCP

2. FURAN

3. FURAN
WHATISFURAN?
Furanisanunsaturatedfivememberedheterocyclic
compoundconsistsofoxygenasheteroatomat1
st
position.
Itsvapoursproduceabrightgreencolourwhenbrought
incontactwithapinesplintmoistenedwithcon.HCl.
Molecularformula:C
4H
4O
Furanoccursinwood-tar.

4. SYNTHESIS/ PREPARATION
1)Fromcarbohydrates
MostimportantsourceoffuranisfurfuralPentoses
Acid hydrolysis
O
CHO
Furfural O
CHO
O
Furfural
Furan
+CO
Pd/ C
200°C

5. 2) Paal-Knorr synthesis of furan
Acidcatalyseddehydrationof1,4dicarbonylcompoundsgives
FuranderivativesCH
2
CH
2
CC
O O
R
1
R
C
O
C
CHCH
R
1
R
H
+
-H
2
O

6. 3) Fiest-Benary synthesis
Reactionofα-haloketoneswithβ-ketoesterinpresence
ofbase(butnotammonia)givesfuranderivatives.C CH
3
O
CHCH
3
Cl
+
CH
2
C
O CH
3
COOC
2
H
5
C
O
C
CC
CH
3
CH
3
CH
3
NaOH/ Pyridine
-HCl
-2H
2
O
COOC
2
H
5

7. 4) From Furfural
Oxidationoffurfuralwithpotassiumdichromatetogivefuroic
acidandsubsequentdecarboxylationat200-300°CO
CHO
Furfural
K
2
Cr
2
O
7
O
COOH
Δ
Furoic acid
O
+CO
2
Furan

8. 5) Commercial method
Decarboxylationoffurfuralinsteaminpresenceofsilveroxide
catalystgivesFuran.

9. REACTIONS
1) ELECTROPHILIC SUBSTITUTION REACTION:
Furan undergoes electrophilic substitution reaction at 2
nd
position
C2 attack gives more resonance structures than C3

10. O
Nitration
O
NO
2
SO
3
in pyridine
Sulphonation
O
SO
3
H
Furan
2-nitrofuran
Furan-2-sulphonic acid
Cl
2
Chlorination
O
Cl
2-chlorofuran
O
Br
Br
2
Bromination
HNO
3
(CH
3
CO)
2
O
+2CH
3
COOH
O
ClCl
+
2,5-dichlorofuran
2-Bromofuran

11. V) Friedel-crafts acylationO
COCH
3
CH
3
COOH+
2-acetylfuran
O
Furan
(CH
3
CO)
2
O
SnCl
4

12. Formylation
VI) Gattermann Koch formylation
VII) VilsmeyerformylationO
Furan
CO+
O
CHO
+
AlCl
3
/ CuCl
HCl
Formyl chloride
Furfural DMF- Dimethyl formamide
N
CH
3
CH
3
CHO O
POCl
3
DMF
O
CHO
Furan Furfural

13. 2) Diels-alder reaction
Furanistheleastaromaticofthefive-memberedringheterocyclicsandact
asadiene.
SoitundergoesDiels-Alderreactionwithmaleicanhydridetoforman
additionproduct.ThisadditionoccursacrossC-2andC-5.
PyrroleandThiophenedonotgivethisreactionastheyaremorearomaticin
character.O+ O
O
O
O
O
O
O
Furan Maleic anhydride
(Diels-Alder adduct)(diene)
(dienophile)

14. 3) REDUCTION
4) Gomberg reaction

15. MEDICINAL USES
1)Furosemide
Diureticdrugusedtoreduceextrafluidinthebody(oedema)caused
byconditionssuchasheartfailure,liverdiseasesandkidneydisease.
Thisdrugisalsousedtotreathighbloodpressure.

16. 2)Ranitidine
AH2antagonistusedtotreatulcersofthestomachand
intestines.

17. 3) Nitrofurantoin
An Antibiotic used for treating urinary tract infections caused by
bacteria.

18. 4) Diloxanide furoate
Ananti-protozoaldrugusedtotreatamoebicdysentery.

19. THIOPHENE

20. THIOPHENE
WHATISTHIOPHENE?
Thiopheneisanunsaturatedfivememberedheterocyclic
compoundconsistsofSulphurasheteroatomat1
st
position.
Molecularformula:C
4H
4S
Thiopheneoccursincoal-taralongwithbenzene
Duetoitsclosenessofitsboilingpoint(84°C)withthatof
benzene(80°C),theycan’tbeseparatedbydistillation.
Hencethiopheneisalwayspresentasanimpurityin
commercialbenzene.

21. Indopheninetest:
Presenceofthiopheneinbenzenemaybedetectedbytheappearanceofa
bluecolourwithisatinandconc.Sulphuricacid.
Separationofthiophenefrombenzene:
❖Byrepeatedextractionofmixturewithconcentratedsulphuricacidand
soformsthiophene-2-sulphonicacidwhichissolubleinsulphuricacid.
❖Thiophenecanalsoremovedbyrefluxingthemixturewithmercuric
acetatewhichmercuratesthiopheneeasily.
❖Itcanberegeneratedfromorganomercurycompoundbyheatingwith
hydrochloricacid.
❖ItcanberemovedfrombenzenebyshakingwithRaneyNickel.

22. SYNTHESIS
1) Paal knorrsynthesis
Thecondensationof1,4-dicarbonylcompoundswithphosphorus
pentasulphideinpresenceofsulphuricacidgivesthiophenederivatives.CH
2
CH
2
CC
O O
R
1
R
C
S
C
CHCH
R
1
R
CH
2
CH
2
CC
O S
R
1
R
-H
2
O
P
2
S
5
H
2
SO
4

23. 2) Simmons-Smith synthesis
Reactionofα-oxoketenedithioacetalswithdiiodomethanein
presenceofzincandcoppergivesthiophenederivatives.C
C
O
C
CH
3
H
5
C
6
SC
2
H
5H
5
C
2
S
C
S
CH
CHC
SC
2
H
5
H
5
C
6
CH
2
I
2
Zn - Cu
reflux, 45 mts

24. 3) Hinsbergsynthesis
Thecondensationof1,2-dicarbonylcompoundswithdiethyl
thiodiacetateinpresenceofastrongbasegivesthiophene
derivatives.OO
PhPh
+
S
OO
OC
2
H
5H
5
C
2
O
-2H
2
Ot - BuO
-
K
+
S
OO
PhPh
OC
2
H
5
H
5
C
2
O
Benzil

25. 4) From sodium succinate
Laboratory synthesis consists of heating sodium succinate with
phosphorous trisulphide gives thiophene.CH
2
CH
2
C C
OO
ONaNaO
P
2
S
3
Δ
S
+
2NaPO
2
S+S
Sodium succinate
Thiophene

26. 5) From n-butane (Commercial)
Byreactionofsulphurwithn-butaneinthegasphaseat
650°C+4S 600 °C
S
+3H
2
S
Butane
Thiophene
Sulphur
Hydrogen sulphide
CH
3
CH
2
CH
3
CH
2

27. REACTIONS
1) ELECTROPHILIC SUBSTITUTION REACTION:
Thiophene undergoes electrophilic substitution reaction at 2
nd
position
C2 attack gives more resonance contributing structures than C3

28. S
Nitration
S
NO
2
SO
3
in pyridine
Sulphonation
S
SO
3
H
Thiophene
2-nitrothiophene
Thiophene-2-sulphonicacid
S
Cl
2-chlorothiophene
S
I
HNO
3
(CH
3
CO)
2
O
+2CH
3
COOH
S
ClCl
+
2,5-dichlorothiophene
2-iodothiophene
SO
2
Cl
2
Chlorination
I
2
-HgO
Iodination

29. V) Friedel-crafts acylationS
COCH
3
CH
3
COOH+
2-acetylthiophene
S
Thiophene
(CH
3
CO)
2
O
SnCl
4
VI) ChloromethylationS
S
+
HCHO+HCl
CH
2
Cl
Thiophene 2-Chloromethylthiophene

30. VII) VilsmeyerformylationS
POCl
3
DMF
S
CHO
Thiophene Thiophene-2-aldehyde DMF- Dimethyl formamide
N
CH
3
CH
3
CHO

31. 2) Reaction with organolithium
Thiophenereactswithn-butyllithiumtoyield2-lithiumthiophene
whichfurtherreactswithcarbondioxidetoformthiophene-2-
carboxylicacid.S
+C
4
H
9
Li
S
Li
CO
2
H
3
O
+
S
COOH
Thiophenen-butyllithium 2-lithiumthiophene Thiophene-2-carboxylic acid

32. 3) ReductionS
Na - NH
3
S
S
+
2,3-dihydrothiophene2,5-dihydrothiophene
H
2
- Pd
S
Tetrahydrothiophene
H
2
- Ni
CH
2
CH
2
CH
3
CH
3
+NiS
Butane

33. 4) Oxidation
Thiophenedoesnotoxidised,buttetrahydrothiopheneoxidised
torespectivesulphone.S S
O O
(O)
Tetrahydrothiophene
Sulphone

34. Medicinal uses
1)Cephalothin
Newsemisyntheticantibacterialagentstructurallyrelatedto
Pencillins.
Itiseffectiveagainstpenicillinase-producingstaphylococciaswellas
othergram-positiveandgram-negativeorganisms.

35. 2) Suprofen
ANonsteroidalanti-inflammatorydrug(NSAID).
Itreducespainandinflammationintheeyes.
Usedophthalmicallytopreventpupilconstriction(reducedpupil
size)duringeyesurgery.

36. 3) Methapyrilene
Ithasstrongsedativeeffects.
Anantihistaminedrugformerlyusedasasleep-inducingdrugs.

37. 4) Tiagabine
Antiepilepticdrug,alsocalledasanticonvulsant.
Usedincombinationwithothermedicationtotreatpartial
seizureinadultsandchildren.