CHM557

ORGANIC CHEMISTRY

CHAPTER 2:
ALDEHYDES AND
KETONES II:
NUCLEOPHILIC
ADDITIONS TO THE
CARBONYL GROUP
 COURSE LESSON PLAN
At the end of the chapter, student should
be able to understand

✔ Reactivity of Carbonyl Group; Nucleophilic

Addition
✔ Cyanohydrin Formation; Synthesis of
α-hydroxy acids and hydrolysis of nitriles
✔ Addition of Organometallic Reagents;
Grignard and alkyl lithium reagents
✔ Addition of Water; Hydrates
✔ Addition of Alcohols; Acetals and Hemiacetals
✔ Reaction with amines
✔ The Wittig Reaction
NUCLEOPHILIC
ADDITION
• Nucleophilic Addition to the Carbonyl Groups
- Addition of a nucleophile to a carbonyl carbon occurs
because of the δ+ charge at the carbon
 Nucleophilic Addition
1. Addition of strong nucleophiles such as hydride or Grignard reagents
result in formation of a tetrahedral alkoxide intermediate
- The carbonyl π electrons shift to oxygen to give the alkoxide intermediate
- The carbonyl carbon changes from trigonal planar to tetrahedral
2. Acid catalyst is used to facilitate reaction of weak nucleophiles with
carbonyl groups
- Protonating the carbonyl oxygen enhances the electrophilicity of the
carbon
 Relative Reactivity: Aldehydes versus Ketones

• Aldehydes are generally MORE REACTIVE than ketones towards

nucleophilic addition.

• Reasons:
1. Aldehyde carbonyl groups are more electron deficient (more
electrophilic) than ketone because they have only one alkyl
group (electron-donating group) attached to the carbonyl
carbon.

Carbonyl carbon is more

one alkyl group positive/more electron
(electron-donati deficient/more electrophilic
ng)
2. Carbon on the carbonyl of aldehyde is less bulkier and less
crowded than ketone which cause more accessibility for
nucleophilic attack. The tetrahedral carbon resulting from addition
to an aldehyde is less sterically hindered than the tetrahedral
carbon resulting from addition to a ketone.
 Relative Reactivity: Aldehydes versus Ketones
❑ Ketone is less reactive towards nucleophilic addition than aldehydes.
▪ Reason:
- Ketone contain two alkyl group compared to aldehyde
i) Carbon on the carbonyl of ketone is bulkier and more crowded (cause steric
effect) than aldehyde which cause less accessibility for nucleophilic attack.

ii) Carbon on the carbonyl of ketone is less electrophilic and less attracted to
nucleophilic compare to aldehyde due to attachment of TWO alkyl groups
(electron donating group or electron releasing group) at C=O.
 Effect of benzene ring to the reactivity of aldehydes or ketones
towards nucleophilic addition

❑ The presence of benzene ring which attach directly to the C=O

groups makes the aldehydes or ketones less reactive.

❑ Reason: Electron withdrawing resonance effect of an aromatic ring

makes the C=O less electrophilic.

❑ Example: benzaldehyde is less reactive compared to ethanal.

 Example
Arrange the following compounds in order of decreasing reactivity towards
nucleophilic addition reaction. Explain your answer.

Methanal 3-Methyl-2-butanone Propanal

Methanal > Propanal > 3-Methyl-2-butanone

Reason:
1. Carbon on the carbonyl of 3-methyl-2-butanone is bulkier and more crowded
than methanal and propanal which cause it less accessible for nucleophilic
attack.

crowded

Methanal 3-Methyl-2-butanone Propanal

 Example
Arrange the following compounds in order of decreasing reactivity towards
nucleophilic addition reaction. Explain your answer.

Methanal 3-Methyl-2-butanone Propanal

Methanal > Propanal > 3-Methyl-2-butanone

Reason:
2. Carbon on the carbonyl of 3-methyl-2-butanone is less electrophilic and less
attracted to nucleophilic compare to methanal and propanal due to the
3-methyl-2-butanone is attached to TWO alkyl group (electron donating group or
electron releasing group)

1 alkyl
No alkyl group 2 alkyl
group
groups
 Exercise 1

Arrange the following pairs of compounds in order of increasing

reactivity with a nucleophile. Explain your answers.

a. Acetone, benzaldehyde, ethanal

b. Acetaldehyde and formaldehyde

Cyanohydrins formation:
Synthesis of α-hydroxy
acids and hydrolysis of
nitriles
✔ Aldehydes and ketones react with hydrogen cyanide (HCN) to
produce cyanohydrins.
✔ Cyanohydrin: A functional group in organic compounds in which a
cyano (CN) and a hydroxy group (OH) are attached to the same
carbon atom.
✔ A catalytic amount of cyanide helps to speed the reaction.
Mechanism of The Addition of Hydrogen Cyanide
✔ The cyano group can be hydrolyzed or reduced.

i. Hydrolysis of a cyanohydrin produces an α-hydroxycarboxylic

acid
ii. Reduction of a cyanohydrin produces α,β-aminoalcohol or
α-hydroxyaldehyde

i. Hydrolysis of a cyanohydrin produces an

α-hydroxycarboxylic acid
 ii. Reduction of a cyanohydrin
a. Reduction of cyanohydrin with H2/Raney Ni or LiAlH4/H2O give
α,β-aminoalcohol

β α
or LiAlH4/H2O
• Reduction to a primary amine with an OH group on the β‑carbon.

b. Reduction of cyanohydrin with DIBAL-H produce α-hydroxyaldehyde

α-hydroxyaldehyd
e
Example of hydrolysis of a cyanohydrin

Acidic hydrolysis
converts cyanohydrins
to α-hydroxy acids or
to α,β-unsaturated
acids
Example of reduction of a cyanohydrin

DIBAL, H2O
 Exercise 2
1. Give reagent and condition that involved in reactions I and II.
2. Draw structure of compounds A-C.

3. Draw structure of compound D

Addition of organometallic
reagents: Grignard and
alkyl lithium reagents
1. Reaction of Grignard Reagents with Carbonyl Compounds

Addition of a Grignard reagent to aldehyde or ketone,

followed by protonation (addition of dilute acid or water),
gives an alcohol.
 Mechanism of addition of Grignard reagent

First reaction: The Grignard reagent attacks a carbonyl compound to

form an alkoxide salt

Second reaction: After the first reaction is complete, water or dilute acid is
added to protonate the alkoxide
Alcohols from Grignard Reagents
 2. Reaction of Alkyl Lithium Reagents with Carbonyl
Compounds

• Organolithium reagents react similarly to Grignard reagents.

• Alcohol will produced.
 Exercise 3
Propose the products (A-C) of the dicarbonyl compound below
with the following reagent. Identify reagent D.
 Exercise 4
How would you synthesize this compounds using Grignard
reagent (nucleophilic addition)

1.

2.

3.
Addition of water: Hydrates
o Aldehydes and ketones react with water to yield 1,1-diols
(geminal (gem) diols)
o Hyradation is reversible: a gem diol can eliminate water
 Mechanism of Hydration of Ketones and Aldehydes
Hydration occurs through the nucleophilic addition mechanism, with
water (in acid) or hydroxide (in base) serving as the nucleophile.

1. Acid-Catalyzed Addition of Water

• Protonation of C=O makes it more electrophilic
 Mechanism of Hydration of Ketones and Aldehydes

2. Base-Catalyzed Addition of Water

• The base-catalyzed hydration nucleophile is the hydroxide ion,

which is a much stronger nucleophile than water
 Addition of alcohols:
Acetals and hemiacetals
a. Hemiacetals/hemiketals
• An alcohol adds to an aldehyde, the result is called a hemiacetal
• An alcohol adds to a ketone the resulting product is a hemiketal.

hemiacetal or
hemiketal
Examples

hemiketal

hemiacetal
✔ An aldehyde or ketone dissolved in an alcohol will form an
equilibrium mixture containing the corresponding hemiacetal.

✔ A hemiacetal has a hydroxyl and alkoxyl group on the same carbon.

✔ Acyclic hemiacetals are generally not stable, however, cyclic five-

and six-membered ring hemiacetals are stable.
Mechanism of formation of hemiacetal

1. Catalyzed by acid
2. Catalyzed by base
 1. Example of mechanism for acyclic hemiacetals

Catalyzed by acid
1. Example of mechanism for acyclic hemiacetals (Cont..)
2. Example of mechanism for cyclic hemiacetals
 2. Example of mechanism for cyclic hemiacetals

In the presence of acid

 Exercise 5
Propose the structure of product from the reaction below.
1.

2.

3.

4.
 Exercise 6

Hemiacetals are derived from aldehydes. They are formed by formal

addition of an alcohol to the carbonyl group. An example of a cyclic
hemiacetal can be formed by reacting 4-hydroxybutanal below with a
catalytic amount of acid. Draw the structure of the hemiacetal and
write the plausible mechanism for the transformation.
b. Acetals
• An aldehyde (or ketone) in the presence of two equivalents of
alcohol or excess alcohol and an acid catalyst will form an acetal
and water.
• Formation of the acetal proceeds via the corresponding hemiacetal.
• An acetal has two alkoxyl groups (-OR) bonded to the same carbon.

alkoxyl groups
Examples
Mechanism of Acetals
Formation
 Exercise 7

Suggest the structure of product and write a mechanism for

the reaction.
❑ Acetals are stable when isolated and purified
❑ Acetal formation is reversible
- An excess of water in the presence of an acid catalyst will
hydrolyze an acetal to the corresponding aldehyde (or
ketone)
• Acetal formation from ketones and simple alcohols is less favorable
than formation from aldehydes
• Formation of cyclic 5- and 6- membered ring acetals from ketones
is, however, favorable.
• Such cyclic acetals are often used as protecting groups for aldehydes
and ketones.
• These protecting groups can be removed using dilute aqueous acid.

Formation of cyclic 5-
membered ring acetals
from ketones

Deprotection
 Acetals as Protecting Groups

▪ Acetals hydrolyze under acidic conditions, but stable to

strong bases and nucleophiles.

▪ Acetals are easily made from the corresponding ketones and

aldehydes and easily converted back to the parent carbonyl
compounds.

▪ This interconversion makes acetals attractive as protecting

groups to prevent ketones and aldehydes from reacting with
strong bases and nucleophiles.
 Example of application of protecting group: Selective acetal
formation
• Because aldehydes form acetals more readily than ketones do,
an aldehyde can be protected selectively in the presence of a
ketone.
• It leaves the ketone available for modification under neutral or
basic conditions without disturbing the more reactive aldehyde
group.
• Example: Reduction of a ketone in the presence of a more
reactive aldehyde.

Protect the aldehyde from undergoes

reduction
 Example 1: Reduction of a ketone in the presence of a more
reactive aldehyde

1. Protection of the aldehyde.

- Formation of acetals from aldehydes
 Example 1: Reduction of a ketone in the presence of a more
reactive aldehyde (continued)

2. Reaction and Deprotection

▪ The acetal will not react with NaBH4, so only the ketone will
get reduced.
▪ Hydrolysis conditions will protonate the alcohol and remove
the acetal to restore the aldehyde (deprotection).
Removal of protecting group

Reduction
 Example 2: Reduction of a ketone in the presence of ester

?
Reduction

(Removal of
(Protection of C=O) (Reduction) protecting group)

Reduction without protect the

ketone will cause both ketone
and ester reduce. It is because
ketone is more readily to
reduce by LiAlH4 than ester
Example 3: Reaction of Grignard reagent with ester in the presence of ketone

Ketone is more Reaction with

reactive than ? Grignard
ester reagent

(Protection of C=O)
(Reaction with
Grignard reagent)
2CH3MgBr

(Removal of protecting
group and protonates
the alkoxides)
Example 4: Reaction of Grignard reagent with ketone in the presence of aldehyde

Nucleophilic addition with

Grignard reagent
Note: Aldehyde is more
reactive than ketone towards
nucleophilic attack

(Protection of C=O aldehyde)

(Reaction with
Grignard reagent)

(Removal of protecting
group and protonates
the alkoxides)
 Exercise 8
The chemical transformation below requires the protection of a
carbonyl group. Suggest how you would carry out the following
transformation to prepare target molecule Z.
 Reactions with amines

https://www.masterorganicchemistry.com/2010/05/24/imines-and-
enamines/
 1. NUCLEOPHILIC ADDITION OF AMINES TO α,
β-UNSATURATED CARBONYL COMPOUNDS
✔ 1,4-Addition or Conjugate Addition
Nucleophile is added to the carbon β to the carbonyl, while the hydrogen
is added to the carbon α to the carbonyl.

a. Primary amines α
α
β β

b. Secondary amines α
α
β β
 2. CONDENSATION REATIONS WITH PRIMARY AMINES AND
OTHER MONOSUBSTITUTED DERIVATIVES OF AMMONIA

• Condensation:
- Chemical reaction in which two molecules combine to form a larger
molecule with the elimination of a smaller molecule such as water,
ammonia or hydrogen chloride.
• Aldehydes condense with primary amines and ammonia derivatives
such as hydroxylamine and substituted hydrazines to give imine
derivatives and eliminate a water molecule.
• Imine:
- A nitrogen analog of an aldehyde or ketone in which the C=O group is
replaced by a C=NR group, where R = alkyl, aryl, or H.
 a. Condensation of aldehydes or ketones with primary
amines
▪ Aldehydes and ketones react with primary amines to yield imines.
These reactions occur fastest at pH 4-5.
Mechanism of Imines Formation
 b. Condensation of aldehydes or ketones with
ammonia
▪ Condensation of aldehyde or ketone with ammonia will produce
imines.
▪ This reaction is catalyzed with acid.
c. Condensation of aldehydes or ketones with hydrazine

▪ Hydrazine reacts with aldehydes or ketones to form hydrazones.

 d. Condensation of aldehydes or ketones with
hydroxylamine
▪ Hydroxylamine reacts with aldehydes or ketones to form oximes.
 e. Condensation of aldehydes or ketones with
phenylhydrazine
▪ Phenylhydrazine reacts with aldehydes or ketones to form
phenylhydrazones.
 f. Condensation of aldehydes or ketones
with 2,4-dinitrophenylhydrazine (2,4-DNP)
▪ A solution of 2,4-DNP in methanol and sulphuric acid is called Brady’s
reagent.
▪ Aldehydes or ketones reacts with 2,4-DNP at room temperature to give a
yellow-orange precipitate of 2,4-dinitrophenylhydrazone.
 3. REACTION OF ALDEHYDES OR KETONES WITH
SECONDARY AMINES

▪ Aldehydes and ketones react with secondary amines to yield enamines.

▪ Secondary amines cannot form a neutral imine by loss of a second
proton on nitrogen.
▪ An enamine is formed instead.

(ene + amine = unsaturated amine)

3. REACTION OF ALDEHYDES OR KETONES WITH
SECONDARY AMINES
 Examples (unsymmetrical ketones):

• Reaction of unsymmetrical ketones with secondary amines will

form two enamines products.

Pyrrolidine
(secondary Major product:
amine) less substituted
alkene
Example: Mechanism of enamine formation
Example: Mechanism of formation of cyclic enamine
 4. STORK ENAMINE REACTION
• The Stork enamine reaction is a method for alkylation or acylation of
ketones through intermediates enamines.

• Ketones cannot be directly alkylated or acylated but when treated

with secondary amines they are converted into enamines which can
further react with various reagents.

• Reactions of enamines:
1. Enamines react with alkyl halides forming alkylated carbonyl
compounds
2. Enamine reacts with an acyl halide or an acid anhydride to form
C-acylated compound. The iminium ion that forms hydrolyzes when
water is added, and the overall reaction provides a synthesis of
β-diketones
3. Enamines react with α,β-unsaturated aldehydes or ketones forming
acylated carbonyl compounds through 1,4-addition (conjugate
addition)
The Stork Enamine Synthesis used for Alkylation, Acylation and Conjugate
Addition

Alkyl halide

Alkylated carbonyl
compound

Acyl halide
or acid
anhydride
β-Diketones

α,β-unsaturated
aldehydes or ketones
(conjugate addition/ Acylated carbonyl
1,4-addition) compound
 3 Steps in Stork Enamine Reaction:
1. Formation of the enamine from ketone or aldehyde
2. Reaction with an electrophile (alkyl halide or α,β-unsaturated
aldehyde or ketone) to form an iminium salt
3. Hydrolysis of the iminium salt to reform the aldehyde or
ketone

Example of Alkylation of an Enamine

 Example

(SN2 Alkylation) (Hydrolysis)

kinetic enamine iminium salt ketone

 Steps in Stork enamine
reaction
Step 1: Formation of enamine (ketone or aldehyde react with secondary
amine)

Typically 2o amines for enamine reactions

 Steps in Stork enamine
reaction
Step 2: Reaction with an electrophile (alkyl halide) to form an iminium salt
SN2 Alkylation (Enamine react with R-X)

iminium salt

Step 3: Hydrolysis of the iminium salt to reform the aldehyde or ketone

iminium salt
Mechanism of Stork enamine
reaction
Mechanism of Stork enamine
reaction
Step 1: Formation of enamine
Mechanism of Stork enamine reaction
(continued)

Step 2: Alkylation

iminium salt
 Mechanism of Stork enamine reaction
(continued)
Step 3: Hydrolysis

iminium salt
 Exercise 9
Suggest the structure of product or reagent for the reaction below.

1.

2.
 Exercise 9 (Continued)
Suggest the structure of product or reagent for the reaction below.

3.

4.
 Exercise 10

An example of a cyclic enamine can be formed by reacting

4-aminobutanal below with an acid. Draw the structure of the
cyclic enamine and write the plausible mechanism for the
transformation.
 Exercise 11
Provide the intermediate and final products for the
below reaction.
The Wittig reaction
 The Wittig reaction
• Aldehydes and ketones react with phosphorous ylides to
produce alkenes

• An ylide is a neutral molecule with adjacent positive and

negative charges
 Examples of the Wittig reaction

+ O=P(Ph3)

phosphorous ylide alkenes

+ O=P(Ph3)

phosphorous ylide
alkenes
 Preparation of Phosphorus Ylides
▪ Step 1: Prepared from triphenylphosphine and an unhindered alkyl
halide (SN2 reaction)
▪ Step 2: Treatment with a strong base such as an organolithium reagent
(butyllithium) and NaNH2. Base (B-) abstracts a hydrogen from the
carbon attached to phosphorus.
Step 1: SN2 reaction

Triphenylphosphine unhindered alkyl

An alkylphenylphosphonium halide
halide

Step 2: Deprotonation

Butyllithium

An alkylphenylphosphonium halide
Ylide
Examples of ylide formation
Step 1: SN2 reaction

Step 2: Deprotonation
Example of ylide formation

Step 1: SN2 reaction

Step 2: Deprotonation
 Mechanism of the Wittig Reaction
• Addition of the ylide to the carbonyl leads to formation of a four-membered
ring oxaphosphetane.
• The oxaphophetane rearranges to the alkene and triphenylphosphine oxide.
• The driving force for the last reaction is formation of the very strong
phosphorus-oxygen double bond in triphenylphosphine oxide.
Example of Wittig reaction
 Retrosynthesis: How to synthesize
2-methyl-1-phenylprop-1-ene by a Wittig reaction

Wittig reaction
?+?

2-Methyl-1-phenylprop-1-ene
 Analysis

or
 Synthesis

The alkyl halide i.e. (CH3)2CHBr is a secondary alkyl halide

The alkyl halide i.e. C6H5CH2Br is a primary alkyl halide

Tips: The ylide should come from an unhindered alkyl halide such as unhindered
primary and methyl halides.

So, reaction (b) is preferable.

 Exercise 12
Draw structure the product or reagent or starting compound for the
following reactions

a.

b.

c.

d.
 Exercise 13

Write the synthetic route to prepare this following

compound using Wittig reaction. Start the reaction from
the preparation of ylides.
 Exercise 14
Ketone A can be converted to alkene B in a one-step reaction via route I. It can also be
converted to alkenes B and C via nucleophilic addition with a Grignard reagent followed by
dehydration reaction with sulfuric acid in route II.

a) Provide a suitable reagent for the conversion of ketone A to alkene B in route I above.
b) Suggest the structure of the intermediate in route II and write a mechanism for the
reaction of ketone A with the Grignard reaction.
c) Draw the structure of alkene C and identify which alkene is the major product in route II.
d) If you were assigned to synthesize alkene B from ketone A, which route would you use
for the synthesis? Provide reasons for your choice of synthesis.
 Exercise 15

Consider the following transformation.

a) Provide suitable reagents in routes I and II above.

b) Draw the structures of compounds A, B and C.
c) An alkene can be prepared from the reaction of ketone Q with a phosphorus ylide,
-
(C6H5)3P+ ̶ CH(CH3). Draw the structure of the alkene and hence, write the mechanism for
this transformation.
 Exercise 16

a) Provide suitable reagents (A, D, E and F) for the following transformation.

b) With regards to the schematic diagram above, conversion of compound P to Q

using reagent A produces another carbonyl compound as a side product. Draw
the structure of this side product.
 Exercise 17
Consider the following transformations.

a. Draw the structures of all products (M, N, O and P) in the above transformations.
b. Provide the appropriate Catalyst A, Catalyst B and Reagent (I).