Kimia Organik

Stephanus Satria Wira W, S.Si., M.Sc.

 OUTLINES
1. Introducing carbonyl compounds
2. Synthesis of aldehydes and ketones MOSTLY TAKEN FROM
3. Reaction with H2O and alcohols FESSENDEN & FESSENDEN 1986
4. Reaction with ammonia, primary, and secondary amine AND
5. Reaction with hydrazine compounds MCMURRY 2010
6. Reaction with Grignard reagent
7. Reduction of aldehydes and ketones
8. Tautomerism
9. 1,4-addition of α,β-unsaturated carbonyls: electrophilic and nucleophilic
 Introducing Carbonyl Compounds
Carbonyl and carboxyl: knowing the difference

DIFFERENT CHEMICAL
REACTIVITY

Aldehyde Ketone Carboxylic acid What is the importance of the carbonyl group
in drug design?

Carbonyl group Carboxyl group

Carbonyl and carboxyl: reaction sites

Aldehyde and ketone reactivity:
Can be attacked by
an electrophile
< <
sp2

Can be attacked by More

a nucleophile reactive
 Synthesis of Aldehydes and Ketones
Synthesis of Aldehydes and ketones
Aldehydes can be synthesized by oxidizing primary alcohol with a soft oxidizing agent

The oxidizing agent is pyridinium chlorochromate (PCC)

PCC will not oxidize aldehydes to carboxylic acids
Methanol ALDEHYDE
FORMED!

If we use a strong oxidizing agent (K2Cr2O7 or KMnO4),

primary alcohol-aldehyde will transform into
carboxylic acid
Primary alcohol

KETONE
FORMED!

Secondary
alcohol
 Reduction and oxidation of carbonyl groups
a) Oxidation reaction

Commonly used as an oxidizing agent:

(1) KMnO4,NaOH/H+, (2) CrO3 /H+ or Na2Cr2O7 /H+

Aldehyde Carboxylic acid

A very strong oxidizing agent can oxidize

Resistant to oxidation! ketone to carboxylic acid
(Example: KMnO4,NaOH/H+)
Ketone
 Reduction and oxidation of carbonyl groups
b) Reduction reaction

NaBH4 We can also use LiAlH4 in acidic conditions to

H+ reduce aldehyde and ketone!

Aldehyde Primary alcohol

NaBH4 However, NaBH4 is softer than LiAlH4

H+
Example:
Ketone
Secondary
alcohol LiAlH4
H+
Carboxylic acid Primary alcohol
 Reduction and oxidation of carbonyl groups
b) Reduction reaction (cont’d)
The Wolff–Kishner reduction is a reaction used in organic chemistry to convert carbonyl groups into
methylene groups

Alkane
Carbonyl group hydrazone
(aldehyde or ketone)

More examples:

A) B)
1. NH2-NH2 1. NH2-NH2
2. KOH, heat 2. KOH, heat
 Reaction with H2O and alcohols
Remember that H2O and alcohol act as a nucleophile. This reaction is a reversible reaction, propelled
by an acid catalyst.
A) Reaction with H2O

a) c)
WHAT PRODUCT?

b)
ALDEHYDE IS MORE REACTIVE
THAN KETONE!

Could you compare the reaction reactivity of (b) and reaction (c) ??
 Reaction with H2O and alcohols
B) Reaction with alcohol

These reactions mechanism are

almost the same as the previous
reaction (carbonyl with H2O)

Study case:
Aldehyde Hemiacetal Acetal
How would you define the reaction
step to form this compound below?

Ketone
Hemiketal Ketal

A cyclic ketal
 Reaction with ammonia, primary, and secondary amine
A) Reaction of aldehyde/ketone with NH3 and primary amine
This reaction involves two steps reaction, addition of acid catalyst is needed in the second step

Elimination reaction

Ketone IMINE FORMED

Ketone
 Reaction with ammonia, primary and secondary amine
B) Reaction of aldehyde/ketone with secondary amine

ENAMINE
FORMED

Know the difference between imine and enamine:

WHAT IS THE HYDROLYSIS

PRODUCT OF THESE
COMPOUNDS IN ACIDIC
CONDITIONS?
IMINE
ENAMINE
 Reaction of carbonyl groups with hydrazine
Hydrazine acts as a nucleophile and converts aldehydes and ketones to hydrazones. Some
hydrazine-like compounds such as phenylhydrazine and formylhydrazine react in the same mechanism
as hydrazine
Reaction in general (can be catalyzed using an acid):

We have studied lots of reaction mechanisms of the carbonyl

group that reacted with nucleophiles. Think again, you probably
found the “reaction pattern”
Aldehyde
or Hydrazone
ketone
Could you please determine the reaction product?
a) b)
PRODUCT
PRODUCT
 Reaction of carbonyl groups with Grignard reagent
A Grignard reagent is an organomagnesium compound which can be described by the chemical
formula ‘R-Mg-X’ where R = alkyl or aryl group and X = halogen

They exhibit strong nucleophilic qualities and also have the ability to form new carbon-carbon bonds

Examples of Grignard reagents:

It can be noted that Grignard reagents

provide an -R or –Ar anion as the
nucleophile
R= alkyl or aryl group
Synthesis of Grignard reagents:

This compound will act as a nucleophile

 Reaction of carbonyl groups with Grignard reagent
Example of Grignard reaction:

WHAT PRODUCT?

Reaction mechanism of reaction above:

1. Nucleophile attack

This species will then react with H2O

An alkoxide ion
 Reaction of carbonyl groups with Grignard reagent
2. Acid workup (protonation)

Tertiary alcohol formed

Study case:
1. Could you propose the mechanism from Grignard reaction to form primary, secondary, and tertiary alcohol?
2. Could you propose the mechanism to form these compounds?
 Tautomerism: Keto-enol form
What is tautomerism?
Tautomerism is a phenomenon where a single chemical compound tends to exist in two or more
interconvertible structures that are different in terms of the relative position of one atomic nucleus, which is
generally the hydrogen
Consider an example of tautomerism given below:
Are there any chemical species in which
the enol form is more stable than the
keto form?

Some aldehydes/ketones are “non-

enolizable” can you give some examples?
KETO FORM ENOL FORM
(99.9%) (0.01%)

Another example:

I guess you all know guys which form

the more favorable is!
Keto form Enol form
 Tautomerism: Keto-enol form
Tautomerism in acidic conditions:

ENOL FORMED

Tautomerism in basic conditions:

ENOLATE ION ENOL FORMED

 Tautomerism: Keto-enol form
Let’s see more examples:
These compounds below are more stable in enol form. Could you explain why the reason is?

Hints:
1. Internal hydrogen bonding
2. Conjugated structure

1,2-dione compound Cyclohexane-1,2-dione

Factor affecting keto-enol equilibria Example of substituents effect:

1. Internal hydrogen bonding
2. Conjugation/resonance
3. Aromaticity
4. Substituents effect

Enol form (dominant) Keto form Enol form (less dominant)

(WHY)
 Tautomerism: Keto-enol form
Tautomerism in drugs
a) Barbituric acid

1. Antifungal
2. Antimicrobial
3. Sedative
4. Antibacterial

Barbituric acid, a starter compound for producing Barbituric derivatives (Shafiq et al. 2020)
barbiturate derivatives
b) Proxibarbal and Valofane

pH 7.4
These are two drugs used in the treatment
of migraine and cephalea

(Wittekind et al. 1984)

84% 16%
 1,4-Addition of α-β-Unsaturated Carbonyl
What is α-β-unsaturated carbonyl compound?

β THERE ARE TWO

β
SITES OF ADDITION
γ
REACTION
γ α α
Remember the positive partial charge
KETONE ALDEHYDE
of carbon atom on C=O and C=C
(ENONE) (ENAL)

Addition of α-β-unsaturated carbonyl compound

Both enone and enal can undergo 1,4-addition reactions, which are electrophilic and nucleophilic addition If
we closely look at the resonance structures of, let’s say, an enone. The resonance structures are:

partially positive charge! (C-sp2)

 1,4-Addition of α-β-Unsaturated Carbonyl
a) Electrophilic addition
Reaction example:
Why is the Br group not in α position?

Let’s check the reaction mechanism

Reaction mechanism:
Step 1: Protonation of the carbonyl group

More stable carbocation, but why will be attacked

doesn’t the reaction from this
species occur? by the
nucleophile
 1,4-Addition of α-β-Unsaturated Carbonyl
a) Electrophilic addition (cont’d)
Step 2: Nucleophilic attack, forming enol

AN ENOL FORMED!

Step 3: Keto-enol equilibria, forming an aldehyde

THE FINAL PRODUCT

 1,4-Addition of α-β-Unsaturated Carbonyl
b) Nucleophilic addition
An α-β-unsaturated carbonyl can undergo addition reaction such as 1,2-addition and 1,4-addition reaction
Reaction example:
It can be noted that a nucleophile
will first attack the partially positive
charge carbon atom

Nucleophile attack overview: There are two possibilities Depending on the steric
hindrance on the nearby
carbon atom

OR
A nucleophile acting as a
strong base
(LiAlH4 and R-MgX)
A nucleophile attack will attack the C of
on carbon of the A nucleophile attack on the β carbon
carbonyl group
carbonyl group
 1,4-Addition of α-β-Unsaturated Carbonyl
b) Nucleophilic addition (cont’d)
Reaction mechanism:
Step 1: Nucleophilic attack

A carbanion intermediate formed!

Step 2: Protonation to form the enol

THE FINAL
Will be protonated by acid
PRODUCT
(sometimes by the protic solvent)
 Exercise: summarizing reactions
Exercise
4.
1.

2.
How would you determine the reaction step to form these
compounds?
5. 6.

3.

(From Grignard reagent)