Reactions of synthetic importance

Pharmaceutical Organic Chemistry III B.PHARM

1. Pharmaceutical Organic Chemistry III
Reactions of Synthetic
Importance
Presented by
SOWMIYA PERINBARAJ
Assistant Professor
Dept. of Pharmaceutical Chemistry
SVCP

2. CLEMMENSEN REDUCTION

3. Definition
❖ClemmensenReductionwasfirstreportedbyClemmensenParkDavis
in1913.
❖ThereductionofCarbonylgroupsofaldehydesorketonesinto
correspondinghydrocarbonormethylenegroupinpresenceofzinc
amalgamandexcesscon.HClisknownasClemmensenreduction.
❖ALDEHYDES(-CHO)/KETONES(-C=O)
[H]
❖HYDROCARBONS (-CH
2)

4. General reaction
•UsedespeciallyforKetonescontainingphenolicorcarboxylic
groupswhichremainunaffected.RC
R
1
O
Zn/Hg
Con.Hcl
R
C
R
1
H
H
Ketone Alkane

5. MECHANISM
•Step1:ActivationofCarbonylgroupbycon.HCl(acidicmedia)R
R
1
O
H
+
R
R
1
O
+
H
R
C
+
R
1
O
H
Ketone

6. Step 2: Transfer of electrons from zinc and
followed by ProtonationR
C
+
R
1
O
H
+2e
- R
C
–
R
1
O
H
H
+
2
R
C
R
1
OH
2
+
H Zn
2+
zn +
2e
-

7. STEP 3: Loss of waterR
C
R
1
OH
2
+
H
OH
2-
R
C
+
R
1
H
Carbocation

8. Step: 4 Transfer of electrons and followed by
ProtonationR
C
+
R
1
H
2e
-
Zn
R
C
–
R
1
H
H
+
R
C
R
1
H
H
Alkane

9. APPLICATIONS
1) Reduction of cyclic ketonesO
Zn/Hg
Con.HCl
Cyclopentanone Cyclopentane

10. 2) Reduction of Aromatic KetonesCH
3
O
Zn/Hg
Con.HCl
CH
3
Acetophenone
Ethylbenzene

11. 3) In synthesis of Naphthalenei) Zn/Hg Hcl
ii) SOCl
2
AlCl
3
C
O
O
OH
CH
2
O
Cl
C
O
b- Benzoyl Propanoic acid g- Phenyl Butanoyl chloride
a- Tetralone
Con.HCl
Zn/Hg
Δ
Se
Tetrahydro naphthalene
Naphthalene

12. 4) Reduction of α, βunsaturated ketonesCH
3
CH
3
O
Zn/ Hg
Con.HCl
CH
3
CH
3
3-penten-2-one
Pentane
1
2
3
4
5

13. 5) Reduction of Phenolic carbonyl compounds in
which phenolic group remain unaffectedOH O
Zn/Hg
Con.HCl
OH
CH
3
Salicylaldehyde
o-cresol
o
m
p

14. METAL HYDRIDE
REDUCTION

15. INTRODUCTION
•Reductionofmetalhydridesproceedsbytransferofhydrideion[H
-
]tothe
substrate.
•Selectivelyreduceanumberoffunctionalgroupssuchas
✓Carbonyl
✓Carboxylicacid
✓Nitro
✓EsterinpresenceC=Cdoublebounds
•Mostlyusedmetalhydridereducingagentsaresodiumborohydride
(NaBH4)andlithiumaluminiumhydride(LiAlH4)
•LiAlH4–Stongreducingagent
•NaBH4–Mildreducingagent

16. SODIUM BOROHYDRIDE (NaBH4)
•NaBH
4 a mild reducing agent soluble in polar solvents such as
water and alcohols but insoluble in ether.
•Reduces carbonyl groups
•Aldehydes
•Ketones
•Alkyl halides
•Acid chlorides

17. Preparation:
•Prepared by reaction of sodium hydride and trimethoxy
borate.+4 NaH B(OCH
3
)
3
250°C
NaBH
4+3CH
3
ONa
Sodium hydrideTrimethoxy
borate
Sodium
borohydride
Sodium methoxide

18. General ReactionRC
R
1
O
4 +NaBH
4
RCH
R
1
O
4
B
-
Na
+
4H
2
O
RCH
R
1
OH
4++H
3
BO
3
NaOH
Ketone
Secondary alcohol
Boric acid
Sodiumborohydride

19. Mechanism
•Step1:Transferofhydrideion[H
-
],powerfulnucleophilefrom
NaBH
4tothecarbonylgroupwithsimultaneousbindingof
carbonyloxygenwithboronRC
R
1
O
+NaBH
4
RC
R
1
O
Na
+
BH
4
-
H
-
RCH
R
1
O BH
3
–
Na
+
Complex

20. Step 2: Remaining 3H
-
transfer to another 3 molecules of
carbonyl compoundsRCH
R
1
O BH
3
–
Na
+
RC
R
1
O
3
RCH
R
1
O
4
B
-
Na
+

21. Step 3: Hydrolysis to alcoholRCH
R
1
O
4
B
-
Na
+
4H
2
O
RCH
R
1
OH
4
Secondary alcohol
+ H
3
BO
3
NaOH
Boric acid
+

22. APPLICATIONS
•Reduction of Benzaldehyde into Benzyl alcohol
•Reduction of cyclohexanone into cyclohexanolNaBH
4
CHO
CH
2
OH O
NaBH
4
OH

23. •Reduction of 4-nitro-1-butanal into 4-nitro-1-butanol
•Reduction of m-nitrobenzaldehydeinto m-nitrobenzylalcoholNO
2
-CH
2
-CH
2
-CH
2
-CHO
NaBH
4
NO
2
-CH
2
-CH
2
-CH
2
-CH
2
-OH NO
2
CHO
NaBH
4
NO
2
CH
2
OH

24. •Reduction of α, β-Unsaturated aldehydes
•Reduction of Alkyl halidesCH=CH-CHO
NaBH
4
CH=CH-CH
2
OH
Cinnamaldehyde
Cinnamyl alcohol CH
2
-Br
NaBH
4
CH
3
Benzyl chloride
Toluene

25. •Reduction of acid chlorideC=O-Cl
NaBH
4
CH
2
-OH
Benzyl alcohol

26. LITHIUM ALUMINIUM
HYDRIDE

27. INTRODUCTION
•Lithiumaluminiumhydrideisastrongreducingagent.
•Violentlyreactswithpolarsolvents,resultinginliberationof
hydrogengas.Hencethesereactionareconductedindry
ether/THF/Dioxane.
•Reducescarbonylgroups,carboxylicacid,acidchloride,acid
unhydrideandepoxidesintocorrespondingalcohols.
•Alsoreducesamides,nitriles,aliphaticnitrocompoundsinto
correspondingamines.

28. PREPARATION
•Preparedbythereactionofanhydrousaluminium
chloridewithlithiumhydrideindryether/THF.4 LiH + AlCl
3
THF
LiAlH
4
+ 3LiCl

29. GENERAL REACTIONRC
R
1
O
4 +LiAlH
4
RCH
R
1
O
4
Al
-
Li
+
4H
2
O
RCH
R
1
OH
4++LiCl
Ketone
Secondary alcohol
Lithium aluminium
hydride
ether
AlCl
3

30. MECHANISM
•Step1:Transferofhydrideion[H
-
],powerfulnucleophilefrom
LiAlH
4tothecarbonylgroupwithsimultaneousbindingof
carbonyloxygenwithboronRC
R
1
O
+LiAlH
4
RC
R
1
O
Li
+
AlH
4
-
H
-
RCH
R
1
O
Complex
AlH
3
-
Li
+

31. Step 2: Remaining 3H
-
transfer to another 3 molecules
of carbonyl compoundsRCH
R
1
O
RC
R
1
O
3
RCH
R
1
O
4
Al
-
Li
+AlH
3
-
Li
+

32. Step 3: Hydrolysis in presence of
acid to give alcoholRCH
R
1
O
4
Al
-
Li
+
RCH
R
1
OH
4
Secondary alcohol
+
4H
2
O
HCl LiCl + AlCl
3

33. APPLICATIONS
1)Reduction of carbonyl compoundsCH
3
(CH
2
)
5
CHO
LiAlH
4
Ether
CH
3
(CH
2
)
5
OH
1-heptanal 1-heptanol O
LiAlH
4
Ether
OH
Cyclopentanone Cyclopentanaol

34. 2) Reduction of Carboxylic acidsCH
3
CH
2
COOH
LiAlH
4
Ether
Propanoic acid
CH
3
CH
2
CH
2
OH
Propanol
3) Reduction of amidesCH
3
NH
2
O
CH
3
-CH
2
-NH
2
Acetamide ethylamine
LiAlH
4
Ether

35. 4) Reduction of acid chloride
5) Reduction of Nitriles into aminesCH
3
N
LiAlH
4
Ether
CH
3
CH
2
NH
2
Acetonitrile
ethylamine C=O-Cl CH
2
-OH
Benzoyl chloride
Benzyl alcohol
LiAlH
4
ether

36. 6) Reduction of nitro compoundsCH
3
CH-CH
2
-CH
3
NO
2
LiAlH
4
ether
CH
3
CH-CH
2
-CH
3
NH
2
2-nitrobutane
2-aminobutane