Chapter 21: Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Reactions

Carboxylic Acid Derivatives

Z can be:

• Cl → acid chloride

• OCOR → acid anhydride

• OR → ester

• NH₂/NHR/NR₂ → amide

• SR → thioester

5 important Derivatives

1. Acid Halide: Most reactive

2. Acid Anhydride: Two acyl groups connected by oxygen

3. Ester

4. Amide

5. Thioester: Ester with S instead of O

Reactivity Order:

ACID CHLORIDE > ANHYDRIDE > ESTER ≈ THIOESTER > AMIDE

Better leaving group = more reactive derivative

Steric Effect

More groups surrounding the carbonyl —> harder for nucleophile to attack —> less reactive

Nucleophilic Acyl Substitution

1. Nucleophile attacks the carbonyl carbon, the C=O pi electrons move onto oxygen, now you have a tetrahedral intermediate.

2. Carbonyl reforms: The oxygen lone pair moves back down to form C=O, at the same time, leaving group leaves.

General Rule for predicting products: Ask, what nucleophile am i adding? Then replace the leaving group with the Nucleophile

Interconversion rule

A more reactive derivative can be converted into a less reactive derivative, but not the other way around

Acid chlorides

the most reactive. why? Cl⁻ is an excellent leaving group.

Make acid chloride:

RCOOH → RCOCl

Reagent:

SOCl₂

Acid chloride reactions:

RCOCl + H₂O → RCOOH
→ hydrolysis

RCOCl + ROH → RCOOR
→ ester

RCOCl + RNH₂ → RCONHR
→ amide

RCOCl + R₂CuLi → RCOR
→ ketone

RCOCl + LiAlH₄ → RCH₂OH
→ primary alcohol

Acid chloride + amine:

Usually use 2 equivalents amine:

• one attacks

• one neutralizes HCl

Acid Anhydrides

Structure:

RCO–O–COR

Formation:

2 RCOOH → anhydride + H₂O

(dehydration)

Reactions:

Anhydride + ROH → ester

Anhydride + RNH₂ → amide

Ac₂O/pyridine:

Used to acetylate alcohols.

Esters

Structure:

RCOOR′

A. Fischer esterification

RCOOH + R′OH ⇌ RCOOR′ + H₂O

Reagents:

H⁺, heat

Important:

• acid-catalyzed

• reversible

• alcohol oxygen becomes the ester OR oxygen

Ester Hydrolysis

Acidic:

RCOOR′ + H₂O/H⁺ ⇌ RCOOH + R′OH

Reversible.

Basic = SAPONIFICATION ⭐

RCOOR′ + OH⁻ → RCOO⁻ + R′OH

Produces a carboxylate salt + alcohol.

Ester Reduction

RCOOR′ + LiAlH₄ → alcohols

Ester + Grignard

Ester + 2 RMgX → tertiary alcohol

Why 2 equivalents?

1st Grignard → ketone
2nd Grignard → tertiary alkoxide
acid workup → tertiary alcohol

Ester + amine

Ester + RNH₂ → amide

= aminolysis

Amides

Structure:

RCONH₂

or

RCONHR / RCONR₂

Why least reactive?

Nitrogen lone pair → resonance with C=O

↓

carbonyl becomes less electrophilic

↓

N is a poor leaving group

Making amides

Acid chloride + amine:

RCOCl + RNH₂ → RCONHR

Carboxylic acid + amine:

Use:

DCC

RCOOH + RNH₂ + DCC → amide

DCC activates the carboxylic acid.

Important for peptide synthesis.

Amide Hydrolysis

Amide + H₂O → carboxylic acid/carboxylate

Amide reduction

Amide + LiAlH₄ → amine

Ester + LiAlH₄ → alcohol

Amide + LiAlH₄ → amine

thioesters

Structure:

RCOSR′

Think:

ESTER with S instead of O

polymers

Polyamide

Contains repeated:

AMIDE linkages

Example:

Nylon

Polyester

Contains repeated:

ESTER linkages

spectroscopy

IR

C=O: ~1650–1750 cm⁻¹

Ester:

C=O ~1735–1750 cm⁻¹
C–O ~1000–1300 cm⁻¹

Amide:

C=O ~1650–1700 cm⁻¹
N–H present if N–H bonds exist

Acid chloride:

C=O around ~1800 cm⁻¹

Anhydride:

TWO C=O peaks

1 H NMR of Esters

Use:

chemical shift + integration + splitting

Typical ester environments:

CH₃CO–: ~2 ppm

OCH₂–: ~4 ppm

terminal CH₃: ~1 ppm

summary part 1

see image

summary part 2

see image

summary part 3

Carboxylic acid derivatives all contain an acyl group, R–C(=O)–, attached to a leaving group. Their main reaction is nucleophilic acyl substitution: nucleophile attacks the carbonyl → tetrahedral intermediate → carbonyl reforms → leaving group leaves.

Reactivity: acid chloride > anhydride > ester/thioester > amide. Better leaving group and less steric hindrance = greater reactivity.

Acid chloride: RCOCl. Made with SOCl₂. It can become an acid, ester, amide, ketone, or alcohol.

Anhydride: RCO–O–COR. Made by dehydration of acids. Can make esters and amides.

Ester: RCOOR. Made by Fischer esterification or from acid chlorides/anhydrides. Hydrolysis gives acid + alcohol. Base hydrolysis is saponification. LiAlH₄ gives alcohols. Two Grignards give a tertiary alcohol.

Amide: RCONH₂/RCONHR/RCONR₂. Least reactive because nitrogen resonance-stabilizes the carbonyl and is a poor leaving group. Made using acid chlorides + amines or carboxylic acids + DCC. Hydrolysis gives carboxylic acid; LiAlH₄ gives amine.

Thioester: ester with S instead of O; important biologically.

Polymers: polyamide = nylon; polyester = repeated ester units. Step-growth polymerization uses molecules with multiple nucleophilic/electrophilic functional groups.

Spectroscopy: look for the carbonyl C=O in IR, and use ¹H NMR chemical shifts + splitting + integration to identify ester environments.

summary part 4

1. Acid chloride > anhydride > ester > amide

2. Better leaving group = more reactive

3. Nu attacks → tetrahedral intermediate → C=O reforms → LG leaves

4. SOCl₂ → acid chloride

5. Acid + alcohol + H⁺ ⇌ ester + water

6. DCC + acid + amine → amide

7. Acid chloride + alcohol → ester

8. Acid chloride + amine → amide

9. Acid chloride + R₂CuLi → ketone

10. Ester + LiAlH₄ → alcohols

11. Amide + LiAlH₄ → amine

12. Ester + 2 RMgX → tertiary alcohol

final summary

CHAPTER 19

Aldehydes + ketones

Nu attacks C=O

↓

addition

↓

alcohol-type product

CHAPTER 20

Carboxylic acids + nitriles

Focus on:

acidity

pKa

synthesis

nitrile chemistry

CHAPTER 21

Carboxylic acid derivatives

Nu attacks C=O

↓

tetrahedral intermediate

↓

leaving group leaves

↓

NEW CARBOXYLIC ACID DERIVATIVE