LESSON 4

NUCLEOPHILIC SUBSTITUTION TO THE CARBONYL GROUP

 Introduction to carboxylic acids

 Preparation od carboxylic acids by oxidation of alcohols
 Reactivity of carboxylic acids: acidity, reduction, Fischer esterification
 Introduction to carboxylic acid derivatives
 Reactivity of Carboxylic Acid Derivatives
1. Reactivity of Acid Chlorides
2. Reactivity of Acid Anhydrides
3. Reactivity of Esters
4. Reactivity of Amides
 Structure and Reactivity of Nitriles
 Introduction to Carboxylic acids
Carboxylic acids are compounds with a −COOH group. These compounds are abundant in nature,
where they are responsible for some familiar odors. They are also found in a wide range of
pharmaceuticals.
Monocarboxylic acids, compounds containing
one carboxylic acid group, are named with the
suffix“-oic acid”. Examples:

Many simple carboxylic acids have common

names accepted by IUPAC. Examples:

The carbon atom of a carboxylic acid group is sp2 hybridized and therefore exhibits trigonal
planar geometry. Carboxylic acids can form two hydrogen-bonding interactions, allowing
molecules to associate with each other in pairs:
 Preparation of carboxylic acids by oxidation of alcohols:

Primary alcohols:

Secondary alcohols:
 Tertiary alcohols:

No reactive C-H bond adjacent the C-OH group, no oxidation possible without breaking the
structure.

Common oxidizing agents:

One of the most common oxidizing agent of alcohols is chromic acid. There are two main
methods to produce it:
Chromic acid will generally oxidize
a primary alcohol to a carboxylic
acid:

To stop the oxidation at the aldehyde PCC (pyridinium chlorochromate) can be used:

Example:
Both oxidizing agents, chromic acid and PCC, will work with secondary alcohols to give ketones:

O O

OH H ex H CrO O OH
2 4

acetone
OH OH

O
 Reactivity of carboxylic acids
1. Acidity:

As their name implies, carboxylic acids exhibit mildly

acidic protons. This is primarily due to the stability of the
conjugate base, which is resonance stabilized. Treatment
of a carboxylic acid with a strong base, such as sodium
hydroxide, yields a carboxylate salt:

Carboxylate salts are named by replacing the

suffix “ic acid” with “-ate”:
When compared to inorganic acids, such as HCl (pKa= -7) or H2SO4, carboxylic acids are extremely
weak acids. But when compared to most classes of organic compounds, such as alcohols, they are
relatively acidic (pKa values mostly range between 4 and 5).

The presence of electron-withdrawing substituents increases the acidity of a carboxylic acid:

2. Reduction:
Carboxylic acids are reduced to primary alcohols upon treatment with LiAlH4 (acts as a hydride
donor):
Mechanism:
3. Reaction with alcohols: Fischer esterification

Can be removed
from the mixture

The Fischer esterification process is reversible and can be controlled by exploiting Le

Châtelier’s principle. That is, formation of the ester can be favored either by using an
excess of the alcohol (i.e., using the alcohol as the solvent) or by removing water
from the reaction mixture as it is formed.

4. Reaction with SOCl2 (thionyl chloride) to give an acid chloride:

 Introduction to carboxylic acid derivatives

same oxidation state

Acid halides and acid anhydrides are highly reactive and are therefore not very common in nature. In
contrast, esters are more stable and are abundant in nature. Naturally occurring esters, such as the
following three examples, often have pleasant odors and contribute to the aromas of fruits and
flowers:

Amides are abundant in living organisms. For example, proteins are comprised of repeating amide
linkages.
General Reactivity of Carboxylic Acid Derivatives

Acid halides are the most reactive. Two effects basically

must be consider:

Inductive effect Resonance effect

The third resonance structure in the acid chlorine does not

contribute much to the resonance hybrid because the p-
orbital overlap required for a C=Cl bond is not effective.
However, it does in amides. As a consequence, the C-N bond
of an amide has significant double bond character.
Planar geometry of amides
Unlike aldehydes and ketones, carboxylic acid derivatives possess a heteroatom that can
function as a leaving group:

When a nucleophile attacks a carboxylic acid derivative, a reaction in which the

nucleophile replaces the leaving group can occur. This type of reaction is called a
nucleophilic acyl substitution.

Mechanism: two steps

Example:
 Acyl halides: Reactivity
To avoid an acid chloride being converted into an acid, it must be protected from moisture,
because when treated with water, acid chlorides are hydrolyzed to give carboxylic acids.
2. Reaction with alcohols:
When treated with an alcohol, acid chlorides are converted into esters. The mechanism is
analogous to hydrolysis. Pyridine is used as a base to neutralize the HCl as it is produced.

Pyridine

Pyridinium chloride

Example:
3. Reaction with amines:

When treated with ammonia, acid chlorides are

converted into amides.
Pyridine is not used in this reaction, because
ammonia itself is a sufficiently strong base to
neutralize the HCl as it is produced. For this reaction,
two equivalents of ammonia are necessary: one for
the nucleophilic attack and the other to neutralize
the HCl. This reaction also occurs with primary and
secondary amines to produce N-substituted amides.
The mechanism is analogous to hydrolysis.

4. Reduction:
When treated with lithium aluminum hydride, acid chlorides are reduced to give primary alcohols:
Mechanism:

To stop the aldehyde from being reduced to the alcohol, a bulky reducing agent can be used.
Example: tri(t-butoxy) aluminum hydride (LBAH) or DIBAH ([(CH3)2CHCH2]2AlH:
5. Reaction with Organometallic Reagents:

1.

2.
Mechanisms:
1. With RMgX:

2. With R2CuLi:
Lithium dialkyl cuprates, also called Gilman
reagents, can be used to convert acid chlorides
into ketones. The resulting ketone is not
further attacked under these conditions. The
alkyl groups are attached to Cu rather than
Mg, so their carbanionic character is less
pronounced (a C−Cu bond is less polarized
than a C−Mg bond).
5. Reaction with other nucleophiles:
Acid chlorides reactivity: Summary
 Acyl Anhydrides: Reactivity
The reactions of anhydrides are analogous to the reactions of
acid chlorides. The only difference is in the identity of the
leaving group.
Acetic anhydride is often used to acetylate an amine or an alcohol:

Aspirin

Paracetamol
 Esthers: Reactivity

1. Saponification (base catalyzed hydrolysis):

Esters can be converted into carboxylic acids by treatment with sodium hydroxide followed by
an acid. This process is called saponification:

Mechanism:
The Saponificación reaction
 The cleansing action of soap
Applications

(a) Sodium stearate molecule: a soap molecule. (b) The simplified representation
of the molecule that shows a hydrophilic head and a hydrophobic tail.

The cleansing action of soap is the result of

the dual nature of the hydrophobic tail and
the hydrophilic end group. The hydrocarbon
tail is readily soluble in oily substances,
which are also nonpolar, while the ionic
carboxylate group remains outside the oily
surface. When enough soap molecules have
surrounded an oil droplet, the entire system
becomes solubilized in water because the
exterior portion is now largely hydrophilic.
This is how greasy substances are removed
by the action of soap.
 Applications
The cleansing action of soap

(a) Grease (oily substance) is not soluble in water. (b) When soap is added to
water, the nonpolar tails of soap molecules dissolve in grease. (c) Finally, the
grease is removed in the form of an emulsion. Note that each oily droplet
now has an ionic exterior that is hydrophilic.
2. Acid-Catalyzed Hydrolysis:

Mechanism:
4. Reduction:

When treated with lithium aluminum hydride, esters are reduced to yield primary alcohols.

excess

Mechanism:
If the desired product is an aldehyde, then DIBAH (diisobutylaluminium hydride) can be used as a
reducing agent instead of LiAlH4.
4. Reaction with Grignard Reagents:
When treated with a Grignard reagent, esters are reduced to yield tertiary alcohols with the
introduction of two alkyl groups:
Amides
Amide group is very common in nature (Example:
proteins), but also in drugs.

Reactivity:

1. Hydrolysis:

Amides can be hydrolyzed to give carboxylic acids in the presence of aqueous acid, but the
process is slow and requires heating to occur at an appreciable rate.
Amides are also hydrolyzed when heated in basic aqueous solutions, although the process is
very slow.

HO-
The mechanisms are similar to those for the hydrolysis of an ester:
2. Reduction:
When treated with excess LiAlH4, amides are converted into amines.

Mechanism:
Nylon is a polyamide: Applications
 Structure and Reactivity of Nitriles

Nitriles are named by replacing the suffix “ic acid” or “oic acid” with “onitrile”

The electronic structure of nitriles is very similar to that of an alkyne with the main difference being
the presence of a set of lone pair electrons on the nitrogen. Both the carbon and the nitrogen
are sp hydridized which leaves them both with two p orbitals which overlap to form the two π bond
in the triple bond.
Preparation
1. From aldehydes and ketones:

2. From alkyl halides:

Reactivity
1. Hydrolysis:
With an acid:
With a base:
2. Reactions with Grignard Reagents:
A ketone is obtained when a nitrile is treated with a Grignard reagent followed by aqueous
acid.
The Grignard reagent attacks the nitrile, much like it attacks a carbonyl group. The resulting
anion is then treated with aqueous acid to give an imine, which is then hydrolyzed to a ketone
under acidic conditions.

3. Reduction: