SCH 305: FUNCTIONAL GROUP APPROACH IN ORGANIC SYNTHESIS
SYNTHESIS OF CARBONYL COMPOUNDS (ALDEHYDES AND KETONES
➢Aldehydes and ketones can be synthesized using a wide variety of reactions.
1. Oxidation of Alcohols
➢Strong oxidizing agents such as KMnO4,Na2Cr2O7, H2CrO4 oxidize alcohols as
illustrated below
➢ (a) 1° Alcohols are oxidized to aldehydes and then to carboxylic acids
under these harsh reaction conditions.
➢ To oxidize 1° Alcohols to aldehydes, a special oxidizing agent formed by
dissolving Chromium trioxide (CrO3) in HCl treated with pyridine called
Pyridinium chlorochromate (PCC) is used; in the presence of
dichloromethane/methylene chloride CH2Cl2 solvent.
NB: Chromium reduced from Cr(VI) to Cr(IV)
(b)A common method for oxidizing secondary alcohols to ketones uses chromic
acid (H2CrO4) as the oxidizing agent. Chromic acid is prepared by adding chromium
trioxide (CrO3) to aqueous sulfuric acid.
NB: Since secondary alcohols cannot be oxidized beyond the ketones, both KMnO4 and
Na2Cr2O7 can be used to prepare ketones.
2. Ozonolysis of alkenes to form aldehydes and ketones
Ozone is a very reactive allotrope of oxygen. The reaction of ozone with alkenes causes
the oxidative cleaving of the alkene. The carbon-carbon double bonds are replaced with
carbon-oxygen bonds, giving the required carbonyl product via ozonide as shown below.
NB: Unbranched alkenes form aldehydes and not ketones
Zinc dust in water is used.
3. Preparation of aromatic ketones by Friedel‐Crafts acylation. Lewis acid coordinates to the
halogen, and departure of the halogen (as AlCl4–) results in a fairly stable, resonance-stabilized
carbocation known as the “acylium ion”.
NB: Friedel-Crafts alkylation is inferior as rearrangement may occur to form unintended product.
4. Ketones from alkynes
Markovnikov addition of a hydroxyl group to an alkyne forms a ketone. The addition of a
hydroxyl group to an alkyne causes keto enol tautomerism.
5. Ketones from Lithiumdialkylcuprates
6. Reduction of acyl chlorides by mild reducing agents such as lithium
tri‐tert‐butoxy aluminum hydride (LATB—H). The reaction of LiAlH[OC(CH3)3]3 is a
lot more controlled unlike LiAlH4 since it only has one hydride to give and the big
bulky tert-butoxy groups (that’s -OC(CH3)3) help to slow down the reactivity of the
reagent.
7. Reduction of esters and nitriles by reducing agents:
Esters can be converted to aldehydes using diisobutylaluminum hydride (DIBAH)
carried out at -78 oC to prevent reaction with the aldehyde product.
The use of DIBALH as a hydride source
offers an efficient method for the synthesis
of aldehydes as it only contains one hydride
so the addition of one equivalent to a nitrile
at low temperature (-780C) allows for the
conversion to an aldehyde.
SCH 305: FUNCTIONAL GROUP APPROACH IN ORGANIC SYNTHESIS
Physical properties of aldehydes and ketones
A π-bond is formed by the overlap of p-orbitals of carbon and oxygen atoms. The p-
orbitals are present in a plane perpendicular to the plane of the molecule.
➢ Oxygen is more electronegative than carbon hence, it
is polarised.
➢ The dipole-dipole attraction between the molecules of aldehydes and ketones results
in their higher boiling points as compared to the hydrocarbons of similar molecular
weight.
➢ The hydrogen bond between the polar
carbonyl group and water molecules
accounts for the solubility of aldehyde and
ketones in water.
REACTIONS OF CARBONYL COMPOUNDS
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
due to steric and electronic reasons; aldehydes have less steric hindrance at the carbonyl
carbon and have a larger dipole moment on the carbonyl carbon.
➢ Sterically, the presence of two
relatively large substituents in
ketones hinders the approach of
nucleophile to carbonyl carbon
than in aldehydes having only
one such substituent.
➢ Electronically, two alkyl groups
reduce the electrophilicity of the
carbonyl carbon more effectively in
ketones than in aldehyde
➢ Aldehydes and ketones are amphoteric, can react as acids and bases.
➢ The carbonyl group also serves as both an electrophilic and nucleophilic
site.
➢The carbon, because it is electron-poor, is an electrophile: it is a great
target for attack by an electron-rich nucleophilic group.
➢ When a nucleophile attacks an aldehyde or ketone carbon, there is no
leaving group – the incoming nucleophile simply ‘pushes’ the electrons in
the pi bond up to the oxygen; the oxygen acts as a base, abstracting a
proton from a nearby acid group in the solvent, the reaction is called
a nucleophilic addition.
➢Hydrogens bare the same Greek letter as the carbon atoms to which they
are attached. α - Hydrogens are bonded to α - carbons and β hydrogens
are bonded to β carbons.
➢There can be more than one type of alpha hydrogen, or there may be no
alpha hydrogens in a given carbonyl compound.
➢ Enols are isomers of aldehydes or ketones in which one alpha hydrogen has been
removed and replaced on the oxygen atom of the carbonyl group. The resulting
molecule has both a C=C (-ene) and an –OH (-ol) group, so it is referred to as an enol.
➢ Enol formation is called “enolization”. The mechanism whereby enols are formed in
acidic solution is a simple, two step process, Step 1 is simply the protonation of the
carbonyl oxygen to form the conjugate acid of the carbonyl compound.
➢ The second step is the removal of an alpha proton from the conjugate acid by water
acting as the base.
➢ The enol can be generated by either an acid- or a base-catalyzed mechanism
Under Acidic Conditions
The carbonyl oxygen is protonated by an acid to form an intermediate
oxonium compound; base removes an α -hydrogen during the second step
forming a double bond. Deprotonation of an α hydrogen to form an enol.
Under Basic Conditions
A base removes an α hydrogen to form an alkene. The oxygen of the
enolate anion is protonated in the second step to create a neutral enol
and regenerate the base catalyst.
The “Two-Step” Pattern For Addition Reactions To Aldehydes And Ketones
1. Addition of a nucleophile to an aldehyde or ketone
2. Protonation of the negatively charged oxygen with acid
1. Addition reaction of Grignard reagent to a ketone and an aldehyde
2. Addition of organometallic reagents to carbonyl group
3. Reduction of carbonyl group using hydride reagents
Hydride reagents carry hydride ions (H–), the hydrogen acts as a nucleophile . Both NaBH4 and
LiAlH4 reduce aldehydes or ketones to an alcohols.
REACTIONS OF CARBONYL COMPOUNDS CONT…
4. Addition of hydrogen cyanide to carbonyl compounds
Hydrogen cyanide adds across the carbon-oxygen double bond in aldehydes and some
ketones to produce compounds known as cyanohydrin. Hydrogen cyanide must be
produced in situ i.e produced during the reaction by adding HCl to the mixture of
carbonyl compound and excess of NaCN.
2-hydroxy-2-methylpropanenitrile
2-hydroxypropanenitrile:
5. Addition reaction of ammonia and primary amines with carbonyl compounds
General equation:
(Schiff base)
The type of imine formed depends on the substitution of Z; i.e
2,4-dinitrophenyl hydrazine (DNPH) test is the standard test for
determining whether a compound has an aldehyde or ketone,
functional group. 2,4-dinitrophenyl hydrazine in dilute H2SO4
containing methanol solvent (Brady’s reagent) reacts with carbonyl
compound to give a bright orange red or yellow precipitate. Red ppt
signifies aromatic carbonyl cpd while yellow ppt shows an aliphatic
carbonyl cpd.
NB: An acid-catalyzed reaction of ketone or aldehyde with secondary amines produce
enamine compound in which the double bond is between carbon atoms.
6. Deoxygenation of carbonyl compounds
Deoxygenation is a chemical reaction involving the removal of oxygen atoms from a
molecule. Removal of the carbonyl oxygen atom of a ketone or aldehyde and replacing
it with two hydrogen atoms is achieved through Clemmensen reaction and Wolf-Kishner
H
reaction. R R
C O C
R1 R1
H
Carbonyl compound Alkane
a) Clemmensen Reaction
The reaction involves heating carbonyl compound with large excess of amalgamated
zinc (zinc treated with mercury) and HCl.
H
R Z n (H g ) R
C O C
R1 H C l, H 2 O R1
H
C arb o n y l co m p o u n d A lk an e
(b) Wolf-Kishner reaction
The reaction utilizes hydrazine (NH2NH2) as the reducing agent in the presence of
strong base (KOH); the hydrazine is converted to nitrogen gas.
Mechanism of the Wolff-Kishner Reduction
1) Deprotonation of Nitrogen 3) Deprotonation of Nitrogen
2) Protonation of the Carbon
4) Protonation of Carbon
