PREPARATION OF ALDEHYDES
1.
Oxidation of 1o alcohols: RCH2OH → RCHO
In general, aldehydes are more easily oxidized than
alcohols.
RCHO → RCOOH occurs more readily than
RCH2OH → RCHO.
Therefore, very mild oxidizing agents must by used for
the transformation RCH2OH → RCHO.
Examples of mild oxidizing agents are:
(a) chromium trioxide-pyridine complex,
CrO3 . 2
CrO3.2py;
(b) manganese dioxide, MnO2
N
1
PREPARATION OF ALDEHYDES
1.
Oxidation of 1o alcohols: RCH2OH → RCHO
H
Mild oxidizing agents
CrO3.2py
R C OH
are used.
H
R
H
C OH
MnO2
H
C O
R
H
C O
R
H
You are not required to know the mechanisms of these
reactions.
With strong oxidizing agents, e.g. KMnO4, H2CrO4,
1o alcohols are oxidized to carboxylic acids.
R
H
C OH
H
1o alcohol
KMnO 4
R
C O
HO
2
carboxylic acid
PREPARATION OF ALDEHYDES
2. Reduction of acyl chlorides: RCOCl → RCHO
Lithium tri-t-butoxyaluminum hydride is often used
for this reduction.
CH3
H3C C O
H
Li
CH3
Al O C CH3
O
CH3
CH3
H3C C CH3
CH3
LiAlH[OC(CH3)3]3 or LiAlH(OtBu)3;
this is a mild hydride reducing agent.
3
PREPARATION OF ALDEHYDES
2. Reduction of acyl chlorides
R
LiAlH(OtBu)3
C O
.
R
C O
H
Cl
A partial, simplified mechanism for this reaction:
R
C
Cl
R
O
C
Cl
H
O Li
R
C O
H
+ LiCl
"H "
4
PREPARATION OF CARBONYL COMPOUNDS
B. Preparation of ketones
1. Oxidation of 2o alcohols yields ketones.
R'
R'
[O]
R C OH
C O + "2H"
R
H
2o alcohol
ketone
2.Ketones are formed by addition of H2O to alkynes
R C C R'
alkyne
dil. H2SO4, HgSO4
R'
C O
R
ketone
5
PREPARATION OF CARBONYL COMPOUNDS
B. Preparation of ketones
3. Replacement of chloride in acyl chlorides by nucleophilic
alkyl groups of organocadmium compounds or lithium
dialkylcuprates produces ketones
R
R
C O
+
R'-Cd-R'
R'
Cl
acyl chloride organocadmium
C O + R'-Cd-Cl
ketone
4. Ozonlysis of geminally substituted alkenes yields
ketones.
R
R''
C
R'
C
R'''
O3
R
C
R'
O + O
R''
C
R'''
6
PREPARATION OF KETONES
1. Oxidation of 2o alcohols
R
R'
C OH
H
o
2 alcohol
H2CrO4
R'
C O
R
ketone
The most commonly used reagent for this
oxidation is H2CrO4, chromic acid (Jones
reagent), prepared from CrO3 and H2SO4;
in H2CrO4 , chromium is in the + 6 oxidation
state.
7
PREPARATION OF KETONES
1.
Oxidation of 2o alcohols with Jones reagent, H2CrO4
Key steps in the partial mechanism for this oxidation are:
(a) formation of a chromate ester from the alcohol and H2CrO4;
O
R'
R C OH +
O
R'
VI
Cr
H O
H
OH
R
C
O
VI
Cr
OH
+ H2O
H
O
chromate ester
O
(b) decomposition of the chromate ester
O
O
R'
R
C
O
VI
Cr
R'
C O +
OH
IV
Cr
R
H
O
ketone
OH
H O
Cr (III) is eventually formed, and the color of the reaction mixture
changes from orange to green.
8
PREPARATION OF KETONES
2.
R C C R'
Hydration of alkynes
dil. H2SO4,
HgSO4
alkyne
Let R' = H, so the alkyne is terminal:
R C C H
H 2 O, H
R'
C O
R
ketone
O
R C CH 3
H
R C C H
R
H
C C
+
H
R
C C
H
H
H
H O
H
C C
R
H
H
H
H
+ H2O
H
O
C C
R
H
-H
Markovnikov addn of H
H
O
C C
R
H
AN ENOL
9
PREPARATION OF KETONES
2.
Hydration of alkynes
R C C H
O
H2O, H
R C CH3
H
R C C H H2O, H
H
O
C C
R
H
AN ENOL
An enol is a tautomer of a ketone. Tautomers are isomers
which differs only in the location of a hydrogen atom.
H
O
R
H
C
C
H
ENOL
O
TAUTOMERIZATION
H
C
C
H
R
H
KETONE
10
PREPARATION OF KETONES
3.
Replacement of chloride in acyl chlorides by nucleophilic alkyl
groups of (a) organocadmium compounds or
(b) lithium dialkylcuprates.
(a) Acyl chlorides + organocadmiums
R
R
C O
+
R'-Cd-R'
R'
Cl
acyl chloride organocadmium
C O + R'-Cd-Cl
ketone
Organocadmiums are prepared from Grignard reagents
(Cd is less electropositive than Mg)
2R′MgCl + CdCl2 → R′2Cd + 2MgCl2
(b) Acyl chlorides + lithium dialkylcuprates
O
R C Cl + R'2CuLi
O
R' C Cl
11
PREPARATION OF KETONES
4. Ozonlysis of geminally substituted alkenes
R
R''
C
C
R'
R
O3
R''
O + O
C
C
R'
R'''
R'''
Ozonlolysis is cleavage by ozone
O
CH3
CH3
C
H
C
CH3
+ O3
o
~ - 30 C
CH3
2-methyl-2-butene
O
O
CH3
C
H
CH3
MOLOZONIDE
C
O
CH3
H
O
C
O
CH3 REARRANGEMENT
C
CH3
MOLOZONIDE
O
CH3
O
CH3
C
O CH
H
3
OZONIDE
C
12
PREPARATION OF KETONES
4. Ozonlysis of geminally substituted alkenes
CH3
H
CH3
C
C
CH3
2-methyl-2-butene
O
CH3
O
CH3
C
O CH
H
3
OZONIDE
C
(a) Reductive workup of the ozonolysis reaction
O
CH3
C
O
CH3
C
O CH
H
3
ozonide
Zn, HCl
CH3
H
CH3
C O +O
aldehyde
C
CH3
ketone
When one of the substituents of the alkene is H, reductive
workup of the ozonloysis yields an aldehyde functional group
13
at that carbon.
PREPARATION OF KETONES
(b) Oxidative workup of the ozonolysis reaction
O
CH3
C
O
CH3
C
O CH
H
3
ozonide
H2O2, H
CH3
HO
CH3
C O +O
carboxylic acid
C
CH3
ketone
When one of the substituents of the alkene is H, oxidative
workup of the ozonloysis yields a carboxyl group at that
carbon.
Alkene carbons which bear two alkyl
groups always become ketone carbonyls
on ozonolysis.
14
NUCLEOPHILIC ADDITION TO
ALDEHYDES & KETONES δ
C
Oδ
Carbonyl carbons are electrophilic and are susceptible to
attack by nucleophiles under neutral and basic conditions.
Nu
δ
C
δ
O
Nu
C
O
The addition of Grignard reagents to carbonyl compounds is an
example of this type of reaction.
Carbonyl oxygens are nucleophilic are can be attacked by
electrophiles, usually H⊕.
15
NUCLEOPHILIC ADDITION TO
ALDEHYDES & KETONES
The carbonyl oxygen is
nucleophilic, so under
acidic conditions:
δ
C
δ
O
H
The protonated carbonyl
C
O H
is a hybrid of two
major contributor
resonance forms:
The major contributor is
subject to nucleophilic
attack as shown:
Nu
C
O H
C
C
O H
O H
minor contributor
Nu C
O H
major contributor
NUCLEOPHILIC ADDITION TO CARBONYL CARBON ∴ OCCURS
UNDER BASIC-NEUTRAL CONDITIONS AND UNDER ACIDIC
CONDITIONS
16
ALDEHYDES VS. KETONES
STABILITY AND REACTIVITY
Aldehydes RCδ Oδ
are more reactive and less
H
stable than ketones
Rδ
C
R'
δ
O
for two reasons.
1. In ketones, the δ⊕ on the carbonyl carbon is
stabilized by the electron clouds associated with
two alkyl groups.
2. The carbonyl group in aldehydes is more
C O
sterically accessible than the carbonyl
group in ketones. Some ketones, e.g.
diisopropyl ketone, are very sterically hindered.
17
EXAMPLES OF NUCLEOPHILIC
ADDITION TO ALDEHYDES & KETONES
Addition of HCN (neutral-basic conditions). CN Ө is a
very good nucleophile (ionic nucleophile). The use of
the actual compound HCN is not experimentally feasible,
as it is a lethal gas, bp 26 oC. Addition of the elements of
HCN to a C=O group is effected in two stages, as
follows.
1.
O
C
(i) R
O
R' + C N K
(or Na )
DMSO or DMF
K
R C R'
(dipolar aprotic solvent)
C N
alkoxide (very basic)
K
(ii)
OH
O
R C R' + H
C N
OH
R C R' + KOH
C N
cyanohydrin
18
ADDITION OF HCN TO ALDEHYDES & KETONES
O
(i) KCN, DMSO or DMF
R
C
R'
OH
R C R'
(ii) H2O
C N
cyanohydrin
Cyanohydrins are useful synthetic intermediates.
On treatment with ammonia, the OH group is
converted to an NH2 group, and the nitrile (CN)
group can be hydrolyzed to a carboxyl group.
OH
R C R' NH 3
C N
cyanohydrin
NH 2
R C R'
C N
NH 2
HCl, H 2O
R C R'
HO
C
O
amino acid
19
EXAMPLES OF NUCLEOPHILIC ADDITION TO
ALDEHYDES & KETONES
2.
Addition of bisulfite (saturated aqueous sodium or
potassium bisulfite, NaHSO3 or KHSO3, solution)
Aldehydes and methyl ketones only, undergo this
reaction.HSO3Ө is an ionic nucleophile.
O
R
+
C
H
H2O-insoluble
H O
S
O
O
Na
O
R C
H
H
Na
O
R C
H
O
O
O
S
O
H
H
O
O
O
S
Na
O
Na
R C O S
O
H
H2O-soluble
bisulfite adduct
20
ADDITION OF NaHSO3 TO ALDEHYDES &
METHYL KETONES
O
O
sat'd aq. NaHSO 3
C
R
H
H2O-insoluble
H
O
Na
R C O S
O
H
H2O-soluble
bisulfite adduct
The bisulfite adduct can be hydrolyzed back to the carbonyl
compound.
H
O
O
R C
H
O S
Na
O
O
aqueous acid or base
R
C
H
This two-step sequence is sometimes used to separate
aldehydes or ketones from mixtures with other H2O-insoluble
compounds.
21
EXAMPLES OF NUCLEOPHILIC ADDITION
TO ALDEHYDES & KETONES
3.
Addition of alcohols; this is a typical acid-catalyzed
nucleophilic addition.
O
R
C
OR''
OH
R''OH, H
R C R'
R''OH, H
R C R'
R'
OR''
R' = H: aldehyde
R' = H: ketone
R' = H: hemiacetal
R' = H: hemiketal
OR''
R' = H: acetal
R' = H: ketal
In the next two slides the mechanism of the addition of
two equivalents of an alcohol (R′OH) to an aldehyde
(RCHO), under acidic conditions, is shown.A hemiacetal
is first formed, and the final product is an acetal.
22
ACID-CATALYZED NUCLEOPHILIC ADDITION OF AN
ALCOHOL TO AN ALDEHYDE → ACETAL
(a) Protonation of the aldehyde.
R
O
O
C
C
H
+ H
R
H
protonated aldehyde
H
(b) Nucleophilic addition of the alcohol to the protonated aldehyde
and loss of a proton from the addition product.
The alcohol is a molecular nucleophile (RECALL TUTORIAL #2!!)
H
H
O
O
R
C
H
+ R'
O
- H
OH
R C H
H
R'
O
R C H
H
protonated hemiacetal
R'
O
hemiacetal
23
ACID-CATALYZED NUCLEOPHILIC ADDITION OF
AN ALCOHOL TO AN ALDEHYDE →ACETAL
(c)
Protonation of the OH of the hemiacetal and loss of H2O
H
H
O
O
R C H
+ H
H
R C H
R
- H2O
O
O
R'
hemiacetal
R'
R'
protonated hemiacetal
R
H
C
O
minor contributor
R'
H
C
O
major contributor
(d) Nucleophilic addition of a second equivalent of the alcohol to
the major contributor and loss of a proton from the addition product.
H
R
O
H
C
+ R'OH
R'
O
major contributor
R'
R C H
R'
O
protonated acetal
O
-H
R'
R C H
R'
O
acetal
24
EXAMPLES OF NUCLEOPHILIC ADDITION
TO ALDEHYDES & KETONES
4.
Addition of ammonia and primary amines
R
C
R'
H
N R''
O+
H
pH 3-4
R
C
N R'' + H2O
R'
an imine,
also called
a Schiff base
This reaction can be regarded as a condensation
between the carbonyl compound and ammonia or the
amine to form an imine or Schiff base, with the
extrusion of a molecule of water.
Mechanistically, the process entails nucleophilic addition
of ammonia or the amine (molecular nucleophiles) to the
electrophilic carbon of the carbonyl group.
25
ADDITION OF NH3 AND 1o AMINES
TO ALDEHYDES & KETONES: The mechanism of the reaction
between butanone and methylamine
(a)
Nucleophilic addition of the amine (a molecular nucleophile) to the
carbonyl compound followed by a proton shift within the initial adduct.
O
(Et)
(Me)
C
CH 3 CH 2
CH 3 + CH 3 N
O
H
H
fast
Et
CH 3
C Me
N H
H
(b)
O
fast
Et
CH 3
H
C Me
N
H
Protonation of the addition product on oxygen, followed by loss of H2O,
then deprotonation to yield the IMINE or SCHIFF BASE.
H
H
Me
Et
O
Me
Et
C
H O
C
-H
- H2O
Et C Me + H
Et C Me
N
slow
N
fast
CH3
N
H
CH3
CH3
H
N
26
CH3
H
ADDITION OF NH3 AND 1o AMINES TO ALDEHYDES & KETONES
Amines are basic compounds, and are protonated by acid,e.g.
CH3 N
H
H
methylamine
H
+ H
Cl
CH3 N
H
Cl
H
methylammonium chloride
(an amine salt)
The mechanism shown on the previous slide for the formation
of the Schiff base requires the presence of unprotonated amine
for step (a) and acid for step (b).
HOW IS THIS POSSIBLE IN THE SAME REACTION MIXTURE?
The pH of the reaction mixture is maintained between 3 and 4. At
these pH’s there are high enough concentrations of unprotonated
amine (the molecular nucleophile for the addition step (a)) and acid
to catalyze the dehydration step (b).
27