Carboxylic Acid Derivatives

Question 1

Reactivity of Carboxylic Acids

Answer 1

MOST REACTIVE

Acyl halides

Anhydrides

Esters

Amides

LEAST REACTIVE

Question 2

“Golden Rule”

(from prev chapters)

Answer 2

H- or C- will attack twice, but all other nucleophiles will only attack once

• After attacking a carbonyl, always try to reform the carbonyl if you can, but never kick off H- or C-
• If the second attack is by H- or C-, then the carbonyl will not be able to re-form

Question 3

When can proton transfers happen in an attack?

Answer 3

Between Core steps

*Before the attack * —Attack carbonyl—-> Between attacking & reforming —Reform Carbonyl–> End of mechanism

Question 4

When/Why protonate a carbonyl group?

Answer 4

Why? Makes carbonyl group even more electrophilic

_What: _

Do not need to protonate acyl halides and anhydrides (already reactive enought)

Do need to protonate weakly active onces (ie: ester reacting with water)

Question 5

Fischer Esterification of RCO₂H

Answer 5

Ingredients:

• Carboxylic acid
• Alcohol

RCO2H –MeOH/TsOH–> RCO₂Me

Position of equillibrium is important:

RO₂H —-[Excess ROH, [H+]]—-> RO₂R

RO₂R —-[Excess H₂O, [H+]]—-> RO₂H

Question 6

How do you make Esters from Acyl Halides and Anhydrides?

Answer 6

ROH

Question 7

Ester Hydrolysis under basic conditions

Answer 7

1. -OH attacks Carboxylic acid’s C (C=O pushes to C-O^-)
2. O^- pushes electrons back to C (OR leaves)
3. OH^- depotonates OH so it is O^- [stabilized by resonance]
4. Second step to protonate again. [NOTE: use H+, not H₂O!]

Question 8

Nitriles

Answer 8

• R-C≡N
• Cyano group: [C≡N]
• Same oxidation level of other carboxylic acid derivatives
• Hydrolysis of nitrile produces amide (NOT Ox-Red rxn), can be done under acidic or basic conditions

Question 9

Amide Production

Answer 9

• One core step: Attack the carbonyl
• Hydrolysis of nitrile produces amide (NOT Ox-Red rxn)
• can be done under acidic or basic conditions

Question 10

Reactivity of Carboxylic Acid Derivatives

Answer 10

Question 11

Reactivity of Carboxylic Acid Derivatives (alt view)

Answer 11

Question 12

General Reactions of Carboxylic Acid Derivatives

Answer 12

Question 13

Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexylcarbodiimide (DCC)

Answer 13

1. Dicyclohexylcarbodiimide is first protonated by the carboxylic acid to make it a better acceptor.
2. Thecarboxylatethenadds to the protonated carbodiimide to yield a reactive acylating agent.
3. Nucleophilicattackofthe amine on the acylating agent gives a tetrahedral intermediate.

​The intermediate loses dicyclohexylurea and gives 4 the amide.

Question 14

Reactions of Acid Halides

Answer 14

Question 15

Acid Anhydride Reactions

Answer 15

Question 16

Preparation of Esters

Answer 16

Question 17

Preparation of Amides

Answer 17

Question 18

Nomenclature of Carboxylic Acid Derivatives

Answer 18

Question 19

Hydrolysis

Answer 19

Reaction with water to yeild carboxylic acid

Question 20

Alcoholysis

Answer 20

Reaction with an alcohol to yield an ester

Question 21

Aminolysis

Answer 21

reaction with ammonia or an amine to yield an amide

Question 22

Reduction

Answer 22

reaction with a hydride reducing agent to yield an aldehyde or an alcohol

Question 23

Grignard reaction

Answer 23

Reaction with an organometallic reagent to yield a ketone or an alcohol

Question 24

Summary of Reactions (MM Ch 21.a)

Answer 24

Question 25

Summary of Reactions (MM Ch 21.b)

Answer 25

Question 26

Summary of Reactions (MM Ch 21.c)

Answer 26