Chapter 21.

Carboxylic Acid Derivatives:

Nucleophilic Acyl Substitution Reactions

Intended learning outcomes:

1. To understand the strucuture feature of carboxylic acid
derivatives.
2. To understand the reaction pattern of acyl substitution reactions.
3. To understand the preparation and typical reactions of acid
derivatives.
4. To understand the interconversion of different acid derivatives.
5. To undertand the spectroscopy of acid derivatives.
Carboxylic Compounds

Y= halide acid halides

acyloxy anhydrides
alkoxy esters
amine amides
thiolate thioesters
phosphate acyl phosphates
Benazepril hydrochloride (Novartis Pharma, 1991)

Sales of 1.3 billion USD Benazepril is used to treat

in 2006 high blood pressure
(hypertension)
Nucleophilic Acyl Substitution

[Link]
Relative Reactivity of Carboxylic Acid Derivatives
Steric Factor
More readily with unhindered carbonyl groups

Electronic Factor
More electrophilic carbonyl groups are more reactive to addition ;
Higher reactivity with better leaving group.

[Link]
Nucleophilic Acyl Substitution

• The tetrahedral intermediate having  2 electronegative groups

is relatively unstable

• If either Y or Z is a good leaving group, it tends to restore the C=O unit

• The better leaving group (Z or Y) will be expelled

 The weaker base leaves
 A better leaving group (Y) is a stronger conjugate acid (HY)
[Link]
Nucleophilic Acyl Substitution

a) No replacement Z is a weaker
base than Y

b) Replacement Y is a weaker
base than Z k2 >> k-1
O O O
k1 k2
C + Z R C Y C + Y
R Y k-1 k-2 R Z
Z
the basicities
of Y and Z
c) Equilibrium
are similar
k2  k-1

O O O
k1 k2
C + Z R C Y C + Y
R Y k-1 k-2 R Z
Z
Substitution Reactivity

Why does nature use the amide bond as

the framework of proteins?

Acidity: HCl > RCO2H > R’SH > R’OH > NH3
Basicity: Cl- < RCO2- < R’S- < R’O- < NH2-
An Example on Substitution Reactivity

• Strong base replaces weak base readily

• A much weaker base can not replace the stronger base

Conjugated Acids: HCl (-7); RCOOH (4.8)

O O
C C + Cl no reaction
R O R
an anhydride
General Acyl Substitutions
Acyl Substitution Reactions of Carboxylic Acids
From Acids to Acid Chlorides
with thionyl chloride, SOCl2:
From Acids to Acid Anhydrides

strong heating to remove water:

From Acids to Esters
Basic condition: a carboxylate anion with a primary alkyl halide

Acidic condition (Fischer Esterification): heating a carboxylic acid in an

alcohol solvent in the presence of a small amount of strong acid
Mechanism of the Fischer Esterification
From Acids to Amides

Need activation of the carboxylic acid (COOH) group:

Mechanism
From Acids to Alcohols

LiAlH4

BH3/THF
Reaction Mechanism for BH3 Reduction

The acyl boronate intermediate acts as an activated ester and undergoes

hydride addition twice.

activated ester
BH3: Selective Reduction of Acids
 Acid Halides
Synthesis and Reaction
Synthesis of Acid Halides

By converting the OH into a much better leaving group

(even better than X-)

O O O O
C S C PCl2 C PBr2
R O Cl R O R O

good leaving group

Reactions of Acid Halides
Reactions of Acid Halides
From Acid Halides to Carboxylic Acids and Anhydrides
Hydrolysis  with water to yield carboxylic acids
 HCl is generated: a base is added to remove the HCl

Conversion to anhydrides:
Alcoholysis: From Acid Halides to Esters

With alcohols in the presence of pyridine or NaOH:

Better with less bulky alcohols:

Aminolysis: From Acid Halides to Amides

With NH3, primary (RNH2) and secondary amines (R2NH)

Tertiary amines (R3N) gives an unstable species that cannot be isolated;

HCl is neutralized by the amine or an added base.
Reaction of Acid Halides with Hydride or Organometallic Reagents

LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols:

With Grignard reagents:

Reaction of Acid Halides with Gilman reagent (R2CuLi)

Addition only once

Acid Anhydrides
Synthesis and Reaction
Chemistry of Acid Anhydrides
Preparation of Anhydrides

Symmetrical anhydrides:

Unsymmetrical anhydrides

Cyclic anhydrides
Reactions of Acid Anhydrides: Reactions

Similar to acid chlorides in reactivity

From Anhydrides to Esters and Amides (Acetylation)
 Esters
Synthesis and Reaction
Preparation of Esters
Reactions of Esters

Less reactive toward nucleophiles than acid chlorides or anhydrides

Hydrolysis: With aqueous base or aqueous acid

Reactions of Esters

with amine: Aminolysis

with Grignard reagents:

Reduction: Conversion into Alcohols
Reduction: Conversion into Aldehydes

Note: with DIBAH at -78 oC forms aldehydes (Section 19.2)

Stable at -78oC

Note: with DIBAH at -78 oC forms aldehydes (Section 19.2)

 Amides
Synthesis and Reaction
Introduction to Amides

Amides: abundant in all living organisms…

(proteins, nucleic acids, and other pharmaceuticals)
Preparation of Amides

Prepared by reaction of an acid chloride

with ammonia, primary amines, or secondary amines
Reactions of Amides
Amide is the least reactive carbonyl compound:
From Amides to Acids: Hydrolysis (Acidic Condition)
Under harsh conditions, hydrolysis of amides is possible:
Acidic + heating:

1. Protonation of amino group  make it a better leaving group

2. Protonation of the released amine  kill its nucleophilicity
From Amides to Acids: Hydrolysis (Basic Condition)

Addition of hydroxide and loss of amide ion:

From Amides to Amines: Reduction
Thioesters and Acyl Phosphates

They have biological significance:

Nucleophilic carboxyl substitution in nature often involves a thioester or

acyl phosphate .

most common thioesters in nature

Polyamides and Polyesters

PET
uses: clothing, fibers, tire cord, etc. (Polyethylene
terephthalate)
Summary: Transformation of Acid derivatives

O H
R 2 O
-OC

RN
'
H

H2
R 'O
H2O

R 'N O
H H 2

H O
+
R
' OH

,H
2

2
2

R 'NH
H
O
R'
Spectroscopy of Carboxylic Acid Derivatives
IR – Acid chlorides: near 1800 cm1
– Acid anhydrides: 1820 cm1 and also 1760 cm1
– Esters: 1735 cm1
– Amides: 1650-1690 cm1
Spectroscopy of Carboxylic Acid Derivatives

1H NMR Hydrogens on the carbon next to a C=O are near  2

13C NMR  160 ~180

Practice Problems

7th Ed.
21.32, 21.33, 21.35, 21.36, 21.37, 21.40, 21.42
21.47, 21.48, 21.50, 21.51, 21.52, 21.54, 21.55
21.58, 21.62, 21.65, 21.67, 21.68, 21.69, 21.70

8th Ed.
21.33, 21.31, 21.34, 21.41, 21.36, 21.40, 21.43
21.58, 21.42, 21.55, 21.54, 21.57, 21.61, 21.63
21.65, 21.67, 21.47, 21.51, 21.50, 21.52, 21.71