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Chapter 1: Carbonyl Chemistry Aldehydes and Ketones
Organic Chemistry II Associate ProfessorPhan Minh Giang
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Aldehydes and Ketones
Organic Chemistry II
Classification of carbonyl compounds
Aldehydes and Ketones
IUPAC nomenclature of aldehydes and ketonesMolecular structure and Reactivity of carbonyl group
Nucleophil ic addition to teh carbonyl group
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Natural Aldehydes and Ketones
Organic Chemistry II
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Aldehydes-Ketones
Organic Chemistry II
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IUPAC Nomenclature
Organic Chemistry II
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IUPAC Nomenclature
Organic Chemistry II
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Common Names
Organic Chemistry II
common name(IUPAC name) ( )
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Radico-functional Names
Organic Chemistry II
Radico-functional names of ketones: alkyl alkyl ketone.
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Molecular Structure and Reactivi ty
Organic Chemistry II
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Molecular Structure and Reactivi ty
Organic Chemistry II
water solubili ty
solubilit y in alcohols
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Nucleophilic Additions
Organic Chemistry II
1) Nucleophilic addition to carbon-oxygen double bond
General mechanism
type 1: strong (ionic Nu ) nucleophiles
type 2: weak (neutral NuH, Nu2
H) nucleophiles
Nucleophiles in the addition reactions
O-nucleophiles (H2O, ROH)
N-nucleophiles (ammonia derivatives)
H-nucleophiles (metal hydrides)
C-nucleophiles (organometalic compounds)
2) Relative reactivity: aldehydes and ketones3) Reversibility of the nucleophilic addition
4) Irrevesible addition of hydride reducing agents (NaBH4 and
LiAlH4) and organometallic reagents (RMgX, RLi)
5) Subsequent reactions of the nucleophilic addition: water
elimination (N-nucleophiles)
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
sp2
sp2
Nuc: nucleophile (species with lone pair of electrons) _
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Nucleophilic Addition
Organic Chemistry II
1. Reversibility of the nucleophilic additions
2. Subsequent reactions of addit ion products
C
R
R'
Nu
OH
C
R
R'
C
R
R'
O C
R
R'
Nu
O
H+
H2O Nu
addition product
condensation product(addition-elimination)
Nu:
for O-, H-, or C-
nucleophiles
for N-nucleophiles
tetrahedralintermediatealdehydeketone
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
C
R
R 1
O
Nu:
C
Nu
R
R 1
O
H Nu
Nu:
C
Nu
R
R 1
O H
Type 1: Strong nucleophiles
Nu = ions hydroxide or alkoxide
Irreversible addition reactions
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
Type 2: Weak nucleophiles (Reversible nucleophiles)
C
R
R 1
OH C
Nu
R R 1
OH
H Nu:
C
Nu
R R 1
O H
C
R
R 1
O
H A
C
R
R 1
OH C
R
R 1
OH
H
:A
A:
HA
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
Note: The role of lone pairs on oxygen. The oxygen atom is a strong Lewis base.
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
(Metal hydride)
Summary of nucleophilic additions
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Relative Reactivity
Organic Chemistry II
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Relative Reactivity
Organic Chemistry II
Electronic
Steric Effects
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Relative Reactivity
Organic Chemistry II
Steric effect
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
1. Ozonolysis of alkenes
2. Mercuric-catalyzed hydration of alkynes
3. Friedel-Crafts acylationC-C bond formation method
4. Oxidation of primary and secondary alcohols
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
1) Ozonolysis of alkenes
Example
You can use in the second reduction step: Zn/H2O or Zn/H3O+ .
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
2) Mercuric-catalyzed hydration of alkynes
Example
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
Hydroboration-Oxidation
1. Sia BH2
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
3) Friedel-Crafts acylation
Example
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Synthesis of Aldehydes and Ketones
Organic Chemistry II
4) Oxidation of pr imary and secondary alcohols
Example
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Nucleophilic Addition to >C=O Double Bond
Organic Chemistry II
1) Hydration (addition of water) (O-nucleophile):
Formation of hydrates (gem-diols or 1,1-diols)2) Addition of alcohols (O-nucleophile):
Formation of semi-acetals (hemi-acetals) and acetals
3) Cyclic acetals as protecting group
4) Hydrocyanation (C-nucleophile):
Formation of cyanohydrins5) Addit ion of ammonia derivatives (N-nucleophiles):
Formation of imines
Reversible nucleophiles
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Hydrates, Semiacetals, and Acetals
Organic Chemistry II
O
HO
HO
OH
OH
Sucrose
OR
OR
O
OH
OH
O
CH2OH
OH
O
HO
HO
OH
OH
OH
(+)-GlucoseOH
OR
Carbohydrates: Natural semi-acetals and acetals
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Hydration of Aldehydes and Ketones
Organic Chemistry II
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Hydration of Aldehydes and Ketones
Organic Chemistry II
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Formation of Semiacetals (Hemiacetals)
Organic Chemistry II
semiacetal
Most stable semiacetals are from aldehydes or cyclic ketones
acetal (IUPAC)
(common)
acid-catalyzed (L.A. = Lewis Acid) and
base-catalyzed reactions
RO-
RO -
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Acid-catalyzed Formation of Semiacetals
Organic Chemistry II
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Stable Cyclic Semiacetals
Organic Chemistry II
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Carbohydrates (Sugars)
Organic Chemistry II
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Formation of Acetals
Organic Chemistry II
Problem: Explain why semiacetals, but not acetals, are formed under basic conditions?
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Mechanism of Formation of Acetals
Organic Chemistry II
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Formation of Acetals from Semiacetals
Organic Chemistry II
From semiacetal to acetal: acid-catalyzed step
resonance-
stabilized
cation
semiacetal
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Synthetic Strategy: Acetals as Protecting Groups
Organic Chemistry II
Cyclic acetals are stable in basic medium.
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Synthetic Strategy: Acetals as Protecting Groups
Organic Chemistry II
Ethylene glycol is a common reagent for the protection of aldehydes and
ketones. Carbonyl groups can be protected by converting them into their
acetal forms, and then regenerating them as needed.
O
excess ROHacid catalysis
X
O
Y
OR
X
OR
reagent Y inbase-catalyzed reaction OR
Y
OR
excess wateracid catalysis
Cyclic acetals:- Easy to be formed
- Easy to be removed
- Stable with basic and nucleophilic reagents
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Synthetic Strategy: Acetals as Protecting Groups
Organic Chemistry II
Draw mechanism of the formation of the cyclic acetal.
lone-pair assisted ionization
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Synthetic Strategy: Protecting Groups
Organic Chemistry II
Example Carbonyl compounds can be protected by converting them into
their acetal forms, and then regenerating them as needed.
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Synthetic Strategy: Protecting Groups
Organic Chemistry II
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Synthetic Strategy: Protecting Groups
Organic Chemistry II
Example
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Hydrolysis of Acetals
Organic Chemistry II
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Hydrolysis of Acetals
Organic Chemistry II
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Formation of Cyanohydrin
Organic Chemistry II
-hydroxycarboxylic acid
-hydroxyamine
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Cyanohydrin Formation
Organic Chemistry II
Example
steric hindrancepoor electrophilicicty
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Formation of Imines
Organic Chemistry II
Example
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Formation of Imines
Organic Chemistry II
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Mechanism of Imine Formation
Organic Chemistry II
Mechanism
lone-pair assisted ionization
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Formation of Imines
Organic Chemistry II
lone-pair assisted ionization
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Condensation with Amine Derivatives
Organic Chemistry II
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Oximes and Hydrazones
Organic Chemistry II
Wolff-Kishner Reduction
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Wolff-Kishner Reduction
Organic Chemistry II
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Mechanistic Problems
Organic Chemistry II
Problem: Write a mechanism for the following reaction.
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Mechanistic Problems
Organic Chemistry II
Problem: Write a mechanism for the following reaction.
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Reduction and Oxidation
Organic Chemistry II
1) Metal hydride reduction (H-nucleophiles)
NaBH4LiAlH4
2) Oxidation of aldehydes and ketones
Irreversible nucleophiles
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Metal Hydride Reduction
Organic Chemistry II
Hydride reducing agents (Metal hydrides)
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Metal Hydride Reduction
Organic Chemistry II
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Metal Hydride Reduction
Organic Chemistry II
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Metal Hydride Reduction
Organic Chemistry II
Reduct ion mechanism with NaBH4
O i Ch i t II
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Metal Hydride Reduction
Organic Chemistry II
Reduct ion mechanism with LiAlH4
O i Ch i t II
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Clemmensen and Wolff-Kishner Reduction
Organic Chemistry II
Clemmensen
reduction Wolff-Kishner
reduction
one step reduction
two step reduction
Example: Complete the reductions by filling in your products.
O i Ch i t II
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Metal Hydride Reduction
Organic Chemistry II
Selectivity
O i Ch i t II
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Oxidation of Aldehydes
Organic Chemistry II
General
strong oxidant
weak oxidant
Organic Chemistry II
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Oxidation of Aldehydes
Organic Chemistry II
Organic Chemistry II
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Oxidation of Aldehydes
Organic Chemistry II
Organic Chemistry II
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Reducing and Nonreducing Sugars
Organic Chemistry II
D-Glucose: Semiacetal formationby the intramolecular reaction
Reducing sugars:
positive tests with
Tollens reagent
(aqueous solution of
silver nitrate andammonia) and
Benedict’s reagent
(aqueous solution of
copper (II) hydroxide and
sodium citrate)
reducing sugar
Organic Chemistry II
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Oxidation of Ketones
Organic Chemistry II
heat
strong oxidant
C-C bond break
Baeyer-Villiger
rearrangement
Organic Chemistry II
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Reactions of Multi-functional Compounds
Organic Chemistry II
Problem: Give the structures of the major products formed when citronellal is
treated with each of the following reagents.
Organic Chemistry II
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Reactions of Multi-functional Compounds
Organic Chemistry II
Organic Chemistry II
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Organometallic Reactions (C-nucleophiles)
Organic Chemistry II
Carbanions (C-nucleophiles)
The nature of carbon-metal bond: ionic/covalent.
The carbon can be sp3
, sp2
or sp.1) Grignard reagents
Alkylmagnesium halide: R-MgX
Alkenyl and aryl Grignard reagents: C=CH-MgX, Ar-MgX
Alkynyl Grignard reagents: CC-MgX
2) Organolithium compounds
Alkyllithium: R-Li
Alkenyl lithium: C=CH-Li
Alkynyl lithium: CC-Li
Irreversible nucleophiles
Organic Chemistry II
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Organometallic Reactions
Organic Chemistry II
• The Grignard reaction is an organometallic chemical reaction in which
alkyl, vinyl, or aryl magnesium halides (Grignard reagents) add to a
carbonyl group in an aldehyde or ketone.
• Grignard reagents are similar to organolithium reagents because both
are strong nucleophiles that can form new carbon–carbon bonds.
Grignard reactions and reagents were
discovered by the French chemist Francois
Auguste Victor Grignard (University of Nancy,
France), Nobel Prize in Chemistry in 1912.
Organic Chemistry II
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Organometallic Reactions
Organic Chemistry II
Preparation of Grignard reagents
Organic Chemistry II
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Organometallic Reactions (C-nucleophiles)
Organic Chemistry II
Alcohols f rom Grignard reagents
1) Primary alcohols from formaldehyde
2) Secondary alcohols from aldehydes
3) Tertiary alcohols from ketones4) Carboxylic acids from carbon dioxide
Organic Chemistry II
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Retrosynthetic Analysis
Organic Chemistry II
Retrosynthetic analysis (Disconnection approach):
sequentially break bonds (i.e. diconnect atoms) within
a target structure to reveal the simpler structures.
Organic Chemistry II
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Wittig Reaction: Synthesis of Alkenes
g y
The Wittig reaction was discovered in 1954
by George Wittig, for which he was awarded
the Nobel Prize in Chemistry in 1979.
The Witt ig reaction or Wittig olefination is a chemical reaction of an
aldehyde or ketone with a triphenylphosphonium ylide (often called a
Wittig reagent) to give an alkene and triphenylphosphine oxide.
Organic Chemistry II
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Wittig Reaction: Synthesis of Alkenes
g y
Retrosynthetic analysis
target molecule
Organic Chemistry II
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Wittig Reaction
g y
Organic Chemistry II
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Mechanism of Wittig Reaction
g y
R
R
Phosphonium ylides
Organic Chemistry II
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Wittig Reaction: Synthesis of Alkenes
Retrosynthetic analysis
Organic Chemistry II
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Stereoselectivity of the Nucleophilic Addition
• Stereoselectivity: the preferential formation of one (or more)
products that differ only in their configuration.
• Stereoselectivity can be subdivided into enantioselectivity and
diastereoselectivity.
• Diastereoselectivity occurs when the products which can beformed are diastereomers.
Diastereoselectivity of the Addition of Hydride and
Organometallic Reagents to -Chiral Carbonyl Group
Organic Chemistry II
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Stereoselectivity of the Nucleophilic Addition
When an achiral nucleophilic reagent adds to an achiral aldehyde or
simple acyclic unsymmetrical ketone, a chiral center is formed, but the
two enantiomers are formed in equal amounts.
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
If a chiral center already exists near the carbonyl group, there are
two possible diastereomeric products, and these are in general not
formed in equal amounts.
Organic Chemistry II
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If the substrate is chiral then two diastereomeric transition states occur with
the result that two diastereomeric products are formed in unequal amounts.
Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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• Kinetic nucleophiles (rate control, irriversible): metal hydrides and
organometallic compounds.
• -Chiral carbonyl compounds: carbonyl compounds that contain a
stereocenter in the position to the carbonyl group.
• Cram rule (steric factor): the carbonyl group and the largest substituent
L are placed anti in Newman projection. Group M is of intermediate size
and group S is smallest size.
• Cram chelate model: an -substituent (O or N) and the carbonyl oxygen
chelate a metal cation.
• Felkin-Ahn model: L distances equally from R group and the carbonylgroup, S is close to the trajectory of the nucleophile.
Diastereoselectivity of the Nulceophilic Addition
Organic Chemistry II
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Cram model: hydrocarbon groups or hydrogen at C
Cram chelate model: O- or N-atom at C
and carbonyl group chelate ametal cation
Felkin-Ahn model: O- or N-atom attached to C, non-chelated state
Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
Organic Chemistry II
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Diastereoselectivity of the Nucleophilic Addition
The group containing a heteroatom on the adjacent carbon
atom is held syn coplanar to the carbonyl group
Organic Chemistry II
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Diastereoselectivity of the Addition of Organometallic
Organic Chemistry II
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Diastereoselectivity of the Addition of Hydride
Organic Chemistry II
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Chapter Test: Review 2
Topics
1) IUPAC nomenclature of aldehydes and ketones
2) Synthesis of aldehydes and ketones3) Nucleophilic addition reactions of aldehydes and ketones
4) Synthesis of alcohols and alkenes from aldehydes and ketones
5) Carbon-carbon bond formation: Retrosynthetic analysis of target
products (methods using organometallic reagents and Wittig reaction)
6) Oxidation-reduction reactions of aldehydes and ketones.
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