Aldehydes and ketones

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Aldehydes and Ketones
Nomenclature - form text.
The best way to think of an aldehyde or ketone (or just about any carbonyl compound) is
with a slight positive charge on carbon, and a slight negative charge on oxygen:
R
!
+
!
-
O
Just about all of the chemistry of carbonyl compounds is explained by the oxygen being slightly
nucleophilic (thus easily protonated) and the carbon being strongly electrophilic. Remember
this!
R'
Preparation
:
Aldehydes
:
1) Oxidation of a primary alcohol with PCC
2) Ozonolysis of an alkene
REVIEW IT!
3) Reduction of an Acyl Halide.
Acyl halides can be reduced with a special reagent – lithium tri(
t
-
butoxy)aluminum hydride, LiAl(O
t
-Bu)
3
H :
O
LiAl(
)
3
H
O
R
Cl
R
H
Your text states that aldehydes can be easily prepared from esters with DIBAH
(diisobutylaluminum hydride). Typically, it is easier to reduce all the way to a primary alcohol
(you need 2 equivalents of DIBAH for this), then re-oxidize:
H
O
OH
O
Al
PCC
R
OR'
(Diisobutyl aluminum hydride,
or DIBAH, or DIBAL-H)
R
R
H
Ketones
1) Oxidation of secondary alcohols – usually be the Swern oxidation, or with PCC
2) Ozonolysis of an alkene.
3) Friedel-Crafts Acylation.
Below is the preparation of a ketone sequentially from a primary alcohol (through an
intermediate aldehyde):
O
Li
OH
O
OH
PCC
O
PCC
Some ketones can also be prepared from acyl halides and organo-copper reagents (called
lithium dialkylcuprates), as shown below:
O
O
Li
CuBr
Cu
Li
CuLi
R Cl
R
2
Lithium dialkylcuprate
+ LiBr
Further oxidation of aldehydes and ketones:
As you might imagine, most ketones are inert to all but the harshest oxidative conditions,
and thus there is no synthetic utility in trying to oxidize them. However, aldehydes can generally
be oxidized to carboxylic acids under relatively mild conditions:
O
Ag
2
O / H
2
O
O
R H
NH
4
OH / EtOH
R OH
Reactivity of Aldehydes and Ketones
.
These carbonyl compounds generally have two reaction pathways – they react with
strong nucleophiles (generally, strong nucleophiles have a formal negative charge) under neutral,
generally anhydrous conditions, or with weak nucleophiles (those with lone pairs, but no charge)
under mild acid catalysis. If you take a good look at the nucleophile and reaction conditions,
you’ll be able to figure out which way it will go...
Reactivity – aldehydes are much more reactive than ketones. ‘nuff said.
Addition of water or alcohols (to from a hydrate or alcoholate (ketal)).
Ketones and aldehydes in aqueous or alcoholic media frequently react with the medium
to form hydrates (or alcoholates). The extent to which this occurs correlates to many things,
including the electrophilicity of the carbonyl carbon. While acetophenone exists mostly as the
ketone, trichloroacetaldehyde (chloral) exists almost entirely as the hydrate (if exposed to water):
O
O
HO OH
H
2
O
Very little
O
HO OH
O
Cl
H
H
2
O
Cl
H
Very little
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
 Similar things happen in neutral alcoholic medium - take chloroacetaldehyde in methanol, for
example:
O
HO
OMe
Cl
H
MeOH
Cl
H
Why do these hydrates form better w/ e
-
-withdrawing substituents? Remember the first
figure shown in these notes.....
The mechanism for these additions is relatively straightforward:
O
HO OMe
Cl
H
MeOH
Cl
H
O
Me H
Proton-
transfer
H
Cl
O
O
Me
This is the mechanism for the reaction in neutral media. The mechanism in basic media is left as
an exercise for the reader (i.e.
you
!). In acidic alcoholic media, the reaction behaves like the
Energizerâ„¢ Bunny - it just keeps going and going, until a completely new product is formed. It
is called an acetal:
H
O
HO OMe
MeO
OMe
MeOH
H
3
O
+
Cl
Cl
Cl
H
H
H
The mechanism is quite straightforward:
H
H
O
H
O
H
H
O
H
H
H
H
O
O OMe
MeO OMe
H
Cl
MeOH
H
3
O
+
Cl
Cl
H
H
MeO
OMe
H
Cl
H
H
O
H H
H
H
H
OMe
Cl
O OMe
H
HO O
Cl
Cl
Me
H
Cl
H
H
O
Me H
O
Me H
Basically, a series of protonation, nucleophile attack, deprotonation steps.
Big Note: Acetal formation CANNOT occur under basic catalysis. Convince yourself that this
is true...if you can’t, come see me.
Remember that these reactions are all in equilibrium - it can be forced to the acetal by
doing it under anhydrous conditions (or by distilling off the water), or forced back to the
ketone/aldehyde by the addition of excess water (making it the perfect protecting group!):
O
EtO OEt
EtO OEt
Br
EtO OEt
EtO OEt
O H
EtOH / H
+
Benzene
Br
2
H
2
O / H
+
KOH
1) BuLi
2) Alkylation,
etc.
H
H
H
Br
H
R
H
In general, simple alcohols like methanol and ethanol are not used in the formation of
acetals (particularly from less-reactive ketones!) The main reason is entropy - you’ve got to get
three molecules together to form one - that’s not so good! The very common way around this is
to use a glycol - ethylene or propylene glycol – to form a cyclic acetal:
O
HO
OH
O
O
As you would expect for ethers, acetals are stable to base and most nucleophiles, such as
Grignard reagents and alkyllithiums. They revert back to the carbonyl compound on exposure to
aqueous acid.
TMS
TMS
H
+
/ benzene
TMS
TMS
Enamines:
Just as with alcohols, amines can add to ketones and aldehydes. Primary amines add to
give imines, while secondary amines give enamines (pronounced ene-amines). The reactions are
generally catalyzed by a small amount of acid, and need to be buffered to a pH of ~4.5.
An Imine (in this case, the amine is
hydrazine
, and the product is called a
hydrazone
):
NH
2
O
N
H
2
N NH
2
The mechanism (shown here for cyclobutanone) is pretty straightforward:
N
R
trace H
+
EtOH
N
R
H
2
N NH
2
H
O
H
H
H
NH
2
proton
transfer
NH
2
NH
2
O
O N
HO N
H
2
O N
H
H
H
H
H
O
N
NH
2
N
NH
2
H
In the case of secondary amines, we have a lack of protons that can easily be removed
from the amine – the mechanism thus requires that the offending positive charge be neutralized
by removing a proton from the alkyl group:
O
N H
N
Overall:
N
H
O
H
H
H
O
proton
transfer
O N
HO N
H
2
O N
H
N
N
H
H
O
H
H
No proton on amine to remove!
-> remove proton from former
ketone...
De-Oxygenation reactions.
There are two general reactions for the complete de-oxygenation of ketones and
aldehydes. The general scheme for de-oxygenation is:
O
R' can = H
D
e-Oxygenate
R R'
The two methods are the Wolff-Kishner (runs under basic conditions) and the Clemmensen
(under acidic conditions). Below find an example for each one:
R R'
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