Ketones and Aldehydes
Properties
Nomenclature
Preparation
Reactions
Synthesis
Carbonyl Functional Groups
Large Dipole Controls
Properties and Reactivity
Boiling Points
Dipole-Dipole Interactions
Adrogenic/Anabolic Steroids
CH3 OH
CH3
H
CH3 O
H
CH3
H
O
H
H
H
O
Testosterone
Androstenedione
Anabolic Steroids
CH3 OH
CH3
CH3 OH
H
H
CH3
H
H N
H
N
O
Nandralone
Stanozolol
H
H
IUPAC Nomenclature
Ketones
Cl
O
O
2-methyl-3-pentanone
Cl
2,7-dichlorocycloheptanone
O
Br
1-phenyl-1-propanone
propiophenone (common)
Br
O
(R) 6,6-dibromo-5-cyclopentyl-2-heptanone
OH
Cl
O
(E) 5(S)-hydroxy-1-( m-chlorophenyl)-3-hexen-2-one
O
O
trans 1,3-diacetylcyclohexane
IUPAC Nomenclature
Aldehydes
H
O
O
H
octanal
(E) 3-isopropyl-3-hexenal
O
Br
H
CH
O
cis 4-bromocyclohexane-1-carbaldehyde
O
5-oxohexanal
Classical Aldehyde
Nomenclature
Prefix
form
HCHO
acet
CH3CHO
propion
butyr
valer


CHO

CHO
CHO


CHO
Prefix
capro
CHO
CHO
enanth
capryl
CHO
CHO
pelargon
capr
CHO
CHO
example:
Cl
Cl
classical: -dichloro- -methylenanthaldehyde
IUPAC:
4,4-dichloro-2-methylheptanal
Preparation of Ketones and
Aldehydes
• Friedel-Crafts Acylation (ketones)
• Gatterman-Koch Formylation (aldehydes)
• Hydration of Alkynes (ketones with oxymercuration,
aldehydes with hydroboration)
• Ozonolysis of Alkenes (aldehydes and ketones
depending on substitution)
• 1,3-Dithiane alkylations (aldehydes and ketones)
• Reduction of acids, acid chlorides and
nitriles
• Gilman Reaction (ketones)
Friedel-Crafts Acylation
Isoflavones
Highly Sought After Natural Products
Jamaicin
Piscidia erythrina L.
CH3
CH3
O
O
O
O
CH3O
O
CH3
O
CH3
O
OH
ClCCH2
O
CH3O
O
+
Friedel-Crafts Acylation
A Convergent Synthesis
of Flavonoids
TiCl 4
CH2Cl2
CH3
CH3
O
OH
+ HCl
O
no rxn here
O
CH3O
Price, W.A.; Schuda, P.F. J.Org. Chem., 1987, 52, 1972-1979
O
Acylation occurs ortho to OH
possible complexation
via H bond
CH3
CH3
O

O

H
O


O
CH3O
O
Gatterman-Koch Formylation
O
CH
CO, HCl
AlCl 3/CuCl
benzene or activated benzene needed
in situ preparation of formyl chloride
O
C
O + HCl
HCCl
Oxymercuration Hydration
Markovnikov
OH
CH3CH2C
CH
HgSO 4, H2SO4
H2O
CH3CH2C=CH2
an enol
O
CH3CH2CCH3
a ketone
Hydroboration Hydration
Anti-Markovnikov
CH3CH2C
CH
1) disiamyl borane
2) H2O2, NaOH
B
H
(sia)2BH
OH
CH3CH2CH=CH2
an enol
O
CH3CH2CH2CH
an aldehyde
Ozonolysis
Alkene Cleavage
CH3
CH3
C=C
CH3
H
CH3
CH3
1) O3 in CH 2Cl2
C
2) CH3SCH3
or Zn/HOAc
O +O
C
+ DMSO
CH3
H
DMS
O
O
CH3
O
CH3
C=C
H
CH3
O
H
O
O
O O
H
O
ozonide
Gilman Reagent with
Acid Chlorides
DIBAH
Diisobutyl Aluminum Hydride
Reduction of an Ester to an Aldehyde
O
O
COCH2CH3
1) DIBAH
in toluene
+
2) H3O
CH
+ CH3CH2OH
H
DIBAH
(CH3)2CHCH2
Al
CH2CH(CH3)2
Nucleophilic Addition Reactions:
Strong Nucleophiles

O

+
O
H3O

Nu:
OH
Nu
Nu
Basic nucleophiles: RMgX, RLi, LiAlH 4, NaBH4, RC
Nonbasic nucleophiles: CN
CNa
Carbonyl Reactivity




H
O
C
O
>
H
O
>
C
R
H
O
>
C
R
R'
C
R
decreasing rate of reaction with nucleophile
OR
Cyanohydrin Formation
O
OH
CH
C
HCN, (KCN trace amt.)
H
CN
+ enant.
O
H
CH
CN
Mandelonitrile
in defense glands of
millipede A. corrugata
Nucleophilic Addition Reactions:
Weak Nucleophiles
O
O
+
H , H2O
H
OH
OH2
H
O H
H2O
H3O
+
-H2O
OH
OH
a hydrate
Acetal Formation
O
+
H , CH3OH
HO
OCH3
+
H , CH3OH
OCH3
acetal
hemiacetal
O
CH3CH2O
excess CH3CH2OH, H
CH3O
OCH2CH3
+
+ H2O
Acetal Mechanism
O
+
H , CH3OH
HO
OCH3
+
H , CH3OH
CH3O
OCH3
acetal
hemiacetal
+
-H
+
-H
OH2
O
H
H
HO
OCH3
H2O
H
HO
OCH3 -H2O
OCH3
H
CH3O
HOCH3
HOCH3
OCH3
Propose a Mechanism
O
+
S
S
H3O
H
S
S
H +
Use of Ethylene Glycol to
Protect Ketones and Aldehydes
CH2 CH2
O
+
HOCH2CH2OH, H 3O
O
O
O
+ H2O
O
?
CO2H
CH2OH
Synthesis
O
1) HOCH2CH2OH, H
2) LiAlH 4
3) H3O
+
O
+
CO2H
CH2OH
LiAlH 4 will reduce the ketone preferentially,
therefore, protection of the ketone is necessary.
Aldehydes React Preferentially
O
O
HC
O
CCH3
HC
HOCH2CH2OH
+
H
O
HC
O
O
1) NaBH 4
CCH3
2) H3O
+
OH
CHCH3
Imine Formation
Imines and Enamines
R
O
N
o
1 amine
RNH2
H3O
+ H2O
+
imine
pH = 4-5
o
2 amine
R2NH
H3O
NR2
+ H2O
+
enamine
CH3
N
O
CH3NH2
+ H 2O
+
H3O , pH = 4-5
H2 O
H3 O
O
NH2CH3
intermolec.
+
H transfer
HO
N
+
NHCH3
carbinolamine
CH3
H
-H2O
H2O
NHCH3
Imine Derivatives
Wolff-Kishner Reduction
O
H
NH2NH2, KOH
DMSO
N
NH2
a hydrazone
H
+ N2
Mechanism from Hydrazone
Deoxygenation
Enamine Mechanism
(same as imine mech. until last step)
CH3
CH3
O
N
(CH3)2NH
+
H3O , pH = 4-5
CH3
CH3
N
H
OH2
Wittig Reaction:
C=O into C=C
Ylide Synthesis
(C6H5)3P
(C6H5)3P
+ CH3Br
SN2
(C6H5)3P
CH3 + CH3CH2CH2CH2Li
CH3 Br
(C6H5)3P
CH2
phosphorous ylide
(C6H5)3P
CH2
methylene triphenylphosphorane
Mechanism
(C6H5)3P
CH2
O
(C6H5)3P
CH2
+
HC
(C6H5)3P
CH2
O
C
H
methylene triphenylphosphorane
(C6H5)3P
CH2=CH
(C6H5)3PO +
O
CH2 C
H
an oxaphosphetane
CH3
C
O
(C6H5)3P=C(CH3)2
(CH3)2CHCH2CCH3
CH3
(CH3)2CHCH2CCH3
+ (C6H5)3P=O
Pure Alkene is Formed in Wittig Rxn
CH3
CH2
1) CH3MgBr
O
+
2) POCl3, pyr.
9
:
1
CH2
(C6H5)3P=CH2
methylenecyclohexane
exclusively
(Methoxymethylene)-triphenylphosphorane
an Aldehyde Prep
O
H
OCH3
CH
O
(C6H5)3P
CHOCH3
+
H3O
Propose a Sequence of Steps…
O
CHCH3
O
H
O
H
Provide a Mechanism
O
OCH3
+
H , H2*O
O
*OH
*O is O-18
same
conditions
*
O
HO
H
+ CH3OH
O
OCH3
H
O
+
H , H2*O
+
*OH
same
conditions
*
O
HO
*O is O-18
H
+ CH3OH
H
O
OCH3
H
*
O
HO
+
H
H2O
H2O
- CH3OH
O
*
OH2
O
H
*
OH
H
O
*OH
H
Conjugate Addition to
,-Unsaturated C=O groups
O
O
O
O


2 electrophilic
sites


1,2- vs. 1,4-Addition
CH3
OH
1) CH3MgBr
O
2) H3O

+

O

H
1) Li( CH3)2Cu
2) H3O
+
CH3
Gilman Reagents add 1,4
CH3CH2
O
1) Li( CH3CH2)2Cu
H
2) H3O
CH3CH2
O
+
H
H
CH3CH2
O
Li
H
H
Synthesis
OH
O
??
CN
CH3CH2CH2
Carry Out Conjugate Addition 1st
O
OH
1) Li(CH 3CH2CH2)2Cu
+
2) H3O
CH
CH
CH
3
2
2
3) HCN, (KCN)
CN
MCAD Deficiency, a Genetic
Disease
• Children with any of these enzyme deficiencies
have a significant risk (20%) of death during the
first, clinical episode of hypoglycemia (low blood
glucose).
• Those patients affected show episodes of acute,
life-threatening attacks that are symptomatically
consistent with Reye’s Syndrome and sometimes
misdiagnosed as S.I.D.S.
• The most common of these in-born errors is
MCAD Deficiency. (Medium Chain Acyl-CoA Dehydrogenase)
• ~1/50 Caucasians carry the gene.
MCAD Enzyme
• (MCAD) is one of the enzymes involved in
mitochondrial fatty acid -oxidation, which fuels
hepatic ketogenesis, a major source of energy once
hepatic glycogen stores become depleted during
prolonged fasting and periods of higher energy
demands.
• Typically, a previously healthy child with MCAD
deficiency presents with hypoketotic hypoglycemia,
vomiting, liver dysfunction, skeletal muscle weakness
and lethargy triggered by a common illness. On
average, this occurs between 3 and 24 months of age.
Ackee Fruit
(Bligia Sapida)
from Jamaica
Ingestion of the unripe seeds
from the fruit of the Jamaican
Ackee tree causes a disruption
of the dehydrogenase enzymes
needed to metabolize fatty
acids. This “vomiting sickness”
is a result of the enzyme
inhibitor Hypoglycin A.
CO2H
NH2
(R)(-) MCPA is the Toxic
Metabolite of Hypoglycin-A
CO2H
H
NH2
Hypoglycin-A
from Bligia sapida
metabolism
OH
H
O
(R)(-) MCPA
binds irreversibly to
medium-chain acyl-CoA dehydrogenase enzymes
Wittig Approach to Both
Enantiomers
1) Ph3P=CH2
O
Cl
H
(R)(-)
2) KOC(CH3)3
3) n-BuLi, HCHO
HO
(S )(+) MCPA
(S) via initial S N2
HO
(R)(-) MCPA
(R) via initial epoxide opening
Wittig Approach to (S)(+)-MCPA
Start with (R)(-) Epichlorohydrin
SN2 on 1o Alkyl Chloride?
O
(C6H5)3P=CH2
O
P(C6H5)3
Cl
H
(R)(-)
O
H
P(C6H5)3
KOC(CH3)3
Cl
(S)
O
O
P(C6H5)3
P(C6H5)3
H
(R,R)
(R,R)
Wittig Sequence Affords
(S) (Methylenecyclopropyl)methanol
O
P(C6H5)3
O
P(C6H5)3
(R,R)
(R,R)
O
P(C6H5)3
H
C
O
n-butyl Li
paraformaldehyde
OH
O
P(C6H5)3
H
CH2O
- (C6H5)3PO
OH
(S)
P(C6H5)3
O
Homologation to (S)(-)-MCPA
OH
CN
OSO2CH3
CH3SO 2Cl
KCN
DMF
pyridine
(S)
hydrolysis
or
1) DIBAH
2) CrO3, H2SO 4
(S)
HO2C
(S)
(S)
Approach to (R)-(+)-MCPA
Same Wittig Approach with Ylide
Opening the Epoxide First?
O
O
Cl
Cl
(C6H5)3P
H
(R)
H2C=P(C6H5)3
H
O
O
(C6H5)3P
(R) H
KOC(CH3)3
(C6H5)3P
(S,S)