Oxidation and Reduction and Synthesis

1
ALDEHYDES AND KETONES II.
Oxidation and Reduction and Synthesis
2
CATALYTIC REDUCTION
3
OXIDATION AND REDUCTION
REDUCTION OF ALDEHYDES AND KETONES
2H 2e-
OXIDATION OF ALCOHOLS
- 2H - 2e-
These two reactions are the inverse of each other!
4
MANTRA
REDUCTION OF ALDEHYDES AND KETONES

• Aldehydes react with one mole of reducing
• agent to give a Primary Alcohol
• Ketones react with one mole of reducing
• agent to give a Secondary Alcohol

5
CATALYTIC REDUCTION
H2, 40 o C
Ni, 2 atm
syn addition
Reduction of a CO group is more difficult than
the reduction of a CC double bond.
A specially prepared catalyst called
Raney Nickel is often used for CO.
Often heat and pressure are required.
. and reduction of a benzene ring is more
difficult yet.
6
SELECTIVE HYDROGENATIONS
H2

Conditions will vary with the specific compound.
7
CATALYTIC HYDROGENATION AT 1 ATM
Hydrogen gas is just bubbled through the solution
solvent compound
suspended catalyst
magnetic stir bar
8
ROCKING BOTTLE HYDROGENATION
NOT SHOWN
perforated screen surrounds the bottle
Good for pressures up to about 2 atm.

9
HYDROGENATION BOMB
stirrer
pressure gauge
H2
inlet
head bolts
heavy steel shield
threaded
heater
Good to pressures of 5-10 atm.
thick steel walls
10
HYDRIDE REDUCING REAGENTS
11
Another Method of Reduction
HYDRIDE REAGENTS
simplified mechanism
-
-


sodium borohydride
lithium aluminum hydride
12
THERE IS A DIFFERENCE IN REACTIVITY
more overlap
period 2 element
2sp3 - 1s
NaBH4
B
H
shorter, stronger bond
LESS REACTIVE
more diffuse
less overlap
period 3 element
3sp3 - 1s
H
LiAlH4
Al
longer, weaker bond
MORE REACTIVE
13
COVALENT / IONIC CHARACTER
d-
d
The B-H bond has more covalent character.
B
H
LESS REACTIVE
The Al-H bond has more ionic character and is a
stronger base.

-
H
Al
MORE REACTIVE
14
SODIUM BOROHYDRIDE REDUCTIONS
15
SODIUM BOROHYDRIDE IS SELECTIVE
NaBH4 only reduces aldehydes and ketones
primary alcohol
aldehyde
or R-CH2-OH
ketone
secondary alcohol
The double bond and the ester are not touched.
1
NaBH4
2
H3O
16
SELECTIVE HYDROGENATIONS
A
20O C
1 atm
Pd/C
B
Ni
40O C
H2

2 atm
PtO2
100o C
5 atm
C
Protective group!
A, B, and C progressive
17
Sodium Borohydride Reduction of
Aldehydes and Ketones
aldehyde and ketones
-

workup step
-
alcohol
18
ADDITION IS CONCERTED AND SYN STEREOSPECIFIC
..
..


-
reacts three more times
19
Sodium Borohydride Reduction of Norcamphor
1
NaBH4
2
H3O
exo alcohol (14)
bicyclo2.2.1heptan-2-one (norcamphor)
endo alcohol (86)
20
Sodium Borohydride Reduction of Camphor
1
NaBH4
(exo)
2
H3O
camphor
(endo)
borneol (15)
isoborneol (85)
21
LITHIUM ALUMINUM HYDRIDE REDUCTIONS
22
LiAlH4 (LAH) IS NOT SELECTIVE
LiAlH4 reduces anything with a polar multiple
bond!
d
d-
d
d-
or
CY
C Y
..
As with NaBH4 these compounds give alcohols
aldehyde
ketone
23
LiAlH4 IS NOT SELECTIVE (cont)
These acid derivatives also give alcohols
ester
-OR lost
acid chloride
-Cl lost
carboxylic acid
-OH lost
24
LiAlH4 IS NOT SELECTIVE (cont)
These compounds (all have nitrogen) give amines
amide
oxygen lost
nitrile
no atoms lost

nitro compound
-
oxygens lost
25
SIMPLE ALKENES DO NOT REACT
they are not polar !
or
alkenes
alkynes
.. unless they are conjugated with a polar group.
.. which polarizes them.
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Lithium Aluminum HydrideReduction of
Aldehydes and Ketones
ether
27
REACTION OF HYDRIDES WITH WATER
LiAlH4 Reacts Explosively With H2O, Causing Fire
LiAlH4
4 H2O
LiOH Al(OH)3
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DISSOLVING METAL REDUCTIONS
29
THERMODYNAMIC CONTROL
major
Na
eq
eq
EtOH
ax
locked in eq position
minor
sodium donates electrons and the alcohol donates
protons
.
stereocenters can invert
..
..
..
..
-
OH





e-
e-
H
H
C
.
.
..
-
anion
H
.
radical anion
radical
30
More Thermodynamic Control
Dissolving Metal
major product
Na
EtOH
exo
compare NaBH4 results on slides 18 and 19
major product
Na
EtOH
exo
31
EPIMERIZATION
A stereoisomer that has changed configuration at
only one stereocenter (a type of diastereomer)
is called an EPIMER
strong base
A
B
epimer
NaOtBu
of A
tBuOH
exo
endo
Epimerization generally gives the lowest energy
stereocenter, the one that is most
thermodynamically stable.
endo
epimerization
E N E R G Y
-

..
-
exo
HO-tBu
32
REDUCTION
COMPARISON OF METHODS
33
REDUCTION
THREE DISTINCT METHODS
All methods add two electrons 2e-
CATALYTIC REDUCTION
(gain of electrons reduction)
and two protons 2H.
.
. .
2e- and 2H are added as two H
H H
two radicals
steric control - syn addition
HYDRIDE REDUCTION
proton
H
2e- and 2H are added as H- and H
H-
hydride
steric approach control
DISSOLVING METAL REDUCTION
..
.
-
2e- and 2H are added sequentially as e- ,
H , e- , H

C O
etc.
..
.
H-S
M
M
thermodynamic control
solvent gives proton
metal gives electron
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COMPLETE REMOVAL OF THE CARBONYL GROUP
35
REMOVAL OF CO
THREE METHODS
1) Clemmensen Reduction Zn(Hg) conc. HCl
strong acid conditions
2) Wolff-Kishner Reduction NH2NH2 KOH
strong base conditions
3) Desulfurization
Thioacetal H2 Ni
somewhat milder, but also reduces CC
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Clemmensen Reduction
Removes the CO Group
ZnCl2
Hg

H2O
Exact mechanism is not known.
possibly via
Obviously Zn gives up electrons to Cl
(reduction).
37
Wolff-Kishner Reduction
Removes the CO Group
high-bp solvent
goes via the hydrazone
38
MECHANISM OF THE WOLFF-KISHNER REACTION
(you are not required to memorize this mechanism)
..
..
-


..
..
..
..
..
NaOH
high bp solvent
hydrazone
ketone
..
-

..
-
..
..
..
..
..
-
..
-
CO removed




..
gas
alkane
39
Desulfurization
Removes the CO Group
H2S
40
HOW WOULD YOU DO THESE ?
Wolf-Kishner (base)
Clemmensen (acid)
Desulfurization
Wolf-Kishner (base)
Clemmensen (acid)
Desulfurization