64
Ketones and Aldehydes Properties Nomenclature Preparation Reactions Synthesis
| Date post: | 12-Jan-2016 |
| Category: |
Documents |
| Upload: | roland-alexander |
| View: | 231 times |
| Download: | 1 times |
Ketones and Aldehydes
Properties
Nomenclature
Preparation
Reactions
Synthesis
Carbonyl Functional Groups
Large Dipole Controls Properties and Reactivity
Boiling PointsDipole-Dipole Interactions
Adrogenic/Anabolic Steroids
CH3
O
CH3OH
H
H
H
Testosterone
CH3
O
CH3
H
H
H
O
Androstenedione
Anabolic Steroids
O
CH3OH
H
H
H
CH3
CH3
H
H
HN
N
CH3
OH
H
Nandralone Stanozolol
IUPAC NomenclatureKetones
O
2-methyl-3-pentanone
O
Cl
Cl2,7-dichlorocycloheptanone
O
1-phenyl-1-propanonepropiophenone (common)
OBr Br
(R) 6,6-dibromo-5-cyclopentyl-2-heptanone
OH
O
Cl
(E) 5(S)-hydroxy-1-(m-chlorophenyl)-3-hexen-2-one
O
O
trans 1,3-diacetylcyclohexane
IUPAC NomenclatureAldehydes
O
H
octanal
H
O
(E) 3-isopropyl-3-hexenal
CH
O
Br
cis 4-bromocyclohexane-1-carbaldehyde
O
H
O
5-oxohexanal
Classical Aldehyde Nomenclature
HCHO
CH3CHO
CHO
CHO
CHO
Prefix
form
acet
propion
butyr
valer
CHO
IUPAC: 4,4-dichloro-2-methylheptanal
CHO
CHO
CHO
capro
enanth
capryl
CHOpelargon
CHOcapr
example:CHO
Cl Cl
classical: -dichloro--methylenanthaldehyde
Prefix
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
IsoflavonesHighly Sought After Natural Products
OCH3
CH3
O
OCH3O O
O
Jamaicin
Piscidia erythrina L.
O
CH3
CH3OH
+O
O
ClCCH2
O
CH3O
TiCl4CH2Cl2
O
CH3
CH3OH
O
O
CH3OO
+ HCl
no rxn here
A Convergent SynthesisFriedel-Crafts Acylation
of Flavonoids
Price, W.A.; Schuda, P.F. J.Org. Chem., 1987, 52, 1972-1979
Acylation occurs ortho to OH
OH
O
OCH3
CH3
CH3O
O
O
possible complexationvia H bond
Gatterman-Koch Formylation
CO, HCl
AlCl3/CuCl
CH
O
benzene or activated benzene needed
HCCl
O
C O + HCl
in situ preparation of formyl chloride
Oxymercuration HydrationMarkovnikov
CH3CH2C CHHgSO4, H2SO4
H2OCH3CH2C=CH2
OH
an enol
CH3CH2CCH3
O
a ketone
Hydroboration HydrationAnti-Markovnikov
2) H2O2, NaOH
1) disiamyl borane
O
CH3CH2CH2CH
CHCH3CH2C
an enol
OH
CH3CH2CH=CH2
an aldehyde(sia)2BH
B
H
OzonolysisAlkene Cleavage
C=C
CH3
CH3
CH3
H
O3 in CH2Cl2C O
H
CH3
C
CH3
CH3
O+
H
CH3
CH3
CH3
C=C
OO
O
1)
2) CH3SCH3or Zn/HOAc
OO
O
H O
OO
H
ozonide
DMS
+ DMSO
Gilman Reagent with Acid Chlorides
DIBAHDiisobutyl Aluminum Hydride
Reduction of an Ester to an Aldehyde
COCH2CH3
O
1) DIBAHin toluene
CH
O
+ CH3CH2OH
Al
H
CH2CH(CH3)2(CH3)2CHCH2
DIBAH
2) H3O+
Nucleophilic Addition Reactions:
Strong Nucleophiles
O
Nu:
O
Nu
H3O+ OH
Nu
Basic nucleophiles: RMgX, RLi, LiAlH4, NaBH4, RC CNaNonbasic nucleophiles: CN-
Carbonyl Reactivity
C
O
HH R H
O
CR R'
O
CR OR
O
C> > >
decreasing rate of reaction with nucleophile
Cyanohydrin Formation
CH
O
HCN, (KCN trace amt.)C
OH
HCN
+ enant.
Mandelonitrilein defense glands of millipede A. corrugata
CH
OH
CN
Nucleophilic Addition Reactions:Weak Nucleophiles
O OH
H+, H2O
OH2O
OH
HH
OH
OH
a hydrate
-H2O
H2O
H3O+
Acetal Formation
OH+, CH3OH HO OCH3
hemiacetal
H+, CH3OH OCH3CH3O
acetal
O
excess CH3CH2OH, H+OCH2CH3CH3CH2O
+ H2O
H2O
HOCH3
OCH3CH3O
H
-H2O OCH3HO OCH3
HOH2
HO OCH3
H
HOCH3
OH
acetal
OCH3CH3OH+, CH3OH
hemiacetal
HO OCH3H+, CH3OHO
-H+-H+
Acetal Mechanism
Propose a Mechanism
SS SSH H
O
+H3O+
Use of Ethylene Glycol to Protect Ketones and Aldehydes
O
HOCH2CH2OH, H3O+OO
CH2CH2
+ H2O
?
O
CO2H
O
CH2OH
Synthesis
O
CO2H
O
CH2OHLiAlH4 will reduce the ketone preferentially,
1) HOCH2CH2OH, H+
2) LiAlH4
3) H3O+
therefore, protection of the ketone is necessary.
Aldehydes React Preferentially
CCH3
O
HC
O
CHCH3HC
O OH
HC
OO
CCH3
O
HOCH2CH2OHH+
1) NaBH4
2) H3O+
Imine Formation
Imines and Enamines
O
RNH2
NR
+ H2O
R2NH
NR2
+ H2O
pH = 4-5imine
enamine
1 amine
2 amine
o
o
H3O+
H3O+
-H2O
H2O NCH3H
H2O NHCH3
H3O+
H3O+, pH = 4-5
carbinolamine
intermolec.H+ transfer
HO NHCH3O NH2CH3
+ H2O
NCH3
CH3NH2
O
Imine Derivatives
Wolff-Kishner ReductionO
NH2NH2, KOH
NNH2
a hydrazone
HH
DMSO+ N2
Mechanism from Hydrazone
Deoxygenation
Enamine Mechanism (same as imine mech. until last step)
OH2
NCH3CH3O
(CH3)2NH
H3O+, pH = 4-5
NCH3CH3
H
Wittig Reaction:C=O into C=C
Ylide Synthesis
SN2(C6H5)3P + CH3Br (C6H5)3P CH3
CH3(C6H5)3P + CH3CH2CH2CH2Li (C6H5)3P CH2
CH2(C6H5)3P
phosphorous ylide
Br
methylene triphenylphosphorane
Mechanism
an oxaphosphetane
methylene triphenylphosphorane
+(C6H5)3PO
CH2=CH
(C6H5)3
C
O
CH2
P
H
(C6H5)3
C
O
CH2
P
H
HC
O
+ (C6H5)3P CH2
CH2(C6H5)3P
(CH3)2CHCH2CCH3
O(C6H5)3P=C(CH3)2
(CH3)2CHCH2CCH3
CCH3CH3
+ (C6H5)3P=O
Pure Alkene is Formed in Wittig Rxn
O
CH3
+
CH2
9 : 1
1) CH3MgBr
2) POCl3, pyr.
(C6H5)3P=CH2
CH2
methylenecyclohexane exclusively
(Methoxymethylene)-triphenylphosphoranean Aldehyde Prep
OOCH3H
(C6H5)3P CHOCH3 H3O+
CH
O
Propose a Sequence of Steps…
O O
H H
OCHCH3
Provide a Mechanism
O OCH3H+, H2O
+ CH3OH
O OHHO O
H
**
*O is O-18
* sameconditions
O OCH3H+, H2O
+ CH3OH
O OHHO O
H
**
*O is O-18
* sameconditions
O OCH3
H
O OH2
O OH
H
*
- CH3OHH2O
O OH
H*
H+
H+
HO O
HH
*
H2O
*
Conjugate Addition to,-Unsaturated C=O groups
O O O
O
2 electrophilic sites
1,2- vs. 1,4-Addition
O
1) CH3MgBr
2) H3O+
OHCH3
1) Li(CH3)2Cu
2) H3O+
CH3
O
H
Gilman Reagents add 1,4
O
H
1) Li(CH3CH2)2Cu
2) H3O+
CH3CH2
H
OCH3CH2
H
CH3CH2
H
O
H
Li
Synthesis
O
CN
OH
CH3CH2CH2
??
Carry Out Conjugate Addition 1st
O
CN
OH
CH3CH2CH2
1) Li(CH3CH2CH2)2Cu
2) H3O+
3) HCN, (KCN)
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
NH2H
metabolism
Hypoglycin-A
OH
H O
(R)(-) MCPA
from Bligia sapida binds irreversibly to
medium-chain acyl-CoA dehydrogenase enzymes
Wittig Approach to Both Enantiomers
O
Cl
H
1) Ph3P=CH2
(R)(-)
3) n-BuLi, HCHO2) KOC(CH3)3 HO
(S) via initial S N2
HO
(R) via initial epoxide opening
(S)(+) MCPA
(R)(-) MCPA
Wittig Approach to (S)(+)-MCPAStart with (R)(-) Epichlorohydrin
SN2 on 1o Alkyl Chloride?
O
Cl
H
(C6H5)3P=CH2 KOC(CH3)3O
H
P(C6H5)3
(R)(-)
O
H
P(C6H5)3
Cl
O
P(C6H5)3
(S)
P(C6H5)3
O
(R,R) (R,R)
Wittig Sequence Affords (S) (Methylenecyclopropyl)methanol
O
P(C6H5)3P(C6H5)3
O
(R,R) (R,R)
n-butyl Li
O
P(C6H5)3paraformaldehyde
CH
O
H
O
P(C6H5)3
CH2O
O
P
OH
(C6H5)3
- (C6H5)3POOH
(S)
Homologation to (S)(-)-MCPAOH
(S) (S)
OSO2CH3
CH3SO2Cl
pyridineKCN
DMF(S)
CN
hydrolysisor
1) DIBAH2) CrO3, H2SO4
(S)
HO2C
Approach to (R)-(+)-MCPA Same Wittig Approach with Ylide
Opening the Epoxide First?
O
Cl
H
H2C=P(C6H5)3
ClO
(C6H5)3PH
O(C6H5)3P
H(R)
(R)
KOC(CH3)3
O(C6H5)3P
(S,S)
