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
28
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
34
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
36
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