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
21.2 Nucleophilic Acyl Substitution
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.
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
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

Acidity: HCl > RCO2H > R’SH > R’OH > NH3
Basicity: Cl- < RCO2- < R’S- < R’O- < NH2-
Substitution in Synthesis

• 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
Acyl Substitutions of Carboxylic Acid Derivatives
Acyl Substitution Reactions of Carboxylic Acids
Conversion into Acid Chlorides
with thionyl chloride, SOCl2:
Conversion into Acid Anhydrides

strong heating to remove water:

Conversion into 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
Conversion into Amides

Need activation of the carboxylic acid (COOH) group:

Mechanism
Conversion into Alcohols

LiAlH4

BH3/THF
Chemistry of Acid Halides: Preparation

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
Conversion 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: Conversion into Esters

With alcohols in the presence of pyridine or NaOH:

Better with less bulky alcohols:

Aminolysis: Conversion into 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 with Hydride or Organometallic Reagents

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

With Grignard reagents:

Chemistry of Acid Anhydrides
Preparation of Anhydrides

Symmetrical anhydrides:

Unsymmetrical Anhydrides

Cyclic Anhydride
Chemistry of Acid Anhydrides: Reactions

Similar to acid chlorides in reactivity

Conversion to Esters and Amides (Acetylation)
Chemistry of Esters: Preparation
In-Class Practice Problem

There is another synthetically useful method

for ester preparation:

No strong acid or base, compatible with labile molecules.

(1) Draw resonance structures of CH2N2;

(2) Draw the mechanism of this reaction.

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

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

Chemistry of 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:
Amide 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
Basic Hydrolysis

Addition of hydroxide and loss of amide ion:

Reduction: Conversion into Amines
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

uses: clothing, fibers, tire cord, etc.

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

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

NMR

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