Carbonyl Chemistry 4: Carboxylic Acid Derivatives

Question 1

What are the four classes of carboxylic acid derivatives investigated in this course?

Answer 1

Acyl chlorides
Acid anhydrides
Esters
Tertiary amides

Question 2

Rank the reactivity of the four carboxylic acid derivatives.

Answer 2

1) Acyl chloride
2) Acid anhydride
3) Ester
4) Tertiary amide

Question 3

How do you hydrolyse acyl chlorides?

Answer 3

In water at pH of 7

Question 4

How do you hydrolyse esters?

Answer 4

With either acidic or basic conditions and heat

Question 5

How do you hydrolyse amides?

Answer 5

Strongly acidic or basic conditions and prolonged heating

Question 6

What are the two factors that dictate the relative reactivity of carboxylic acid derivatives?

Answer 6

1) electronegativity of the substituent
2) Resonance stabilisation by lone pairs

Question 7

Why are acyl chlorides so reactive?

Answer 7

Because chlorine is a strongly electronegative substituent group that withdraws electron density
Chlorine is also a larger atom so there is no resonance stabilisation between Cl and C=O

Question 8

What makes acid anhydrides reactive?

Answer 8

O2CR is an electronegative substituent
Strongly withdraws electron density
Oxygen is similar in size to carbon, so there is good interaction between oxygen’s lone pairs and C=O but lone pairs are delocalised into both C=O bonds which weakens the effect (some resonance stabilisation)

Question 9

What makes esters reactive?

Answer 9

OR is electronegative so strongly withdraws electron density
Oxygen is similar in size to carbon so there is strong resonance stabilisation due to interaction between oxygen’s lone pairs and C=O

Question 10

Why are amides the least reactive?

Answer 10

NR2 is a moderately electronegative substituent
Less electron withdrawing than other substituents
Nitrogen is similar size to carbon so there is very strong resonance stabilisation between N lone pairs and C=O

Question 11

What is nucleophilic acyl substitution?

Answer 11

Nucleophilic addition can occur to carbonyls on carboxylic acid derivatives
But they all possess good ‘leaving groups’ that are kicked out leading to the reformation of the C=O bond
So the reaction is overall a substitution

Question 12

What makes a leaving group from a carboxylic acid derivative good?

Answer 12

If they are good at accepting a negative charge - form a stable anion

Question 13

Rank how good the leaving groups are in carboxylic acid derivatives.

Answer 13

1) Acyl chlorides - Cl- anion is stable
2) Acid anhydride - carboxylate anion is stable
3) Ester - OR- group is somewhat stable
4) Tertiary amide - NR2- group is not stable
5) Aldehydes - H- is not a stable leaving group
6) Ketones - CH3- is NOT stable - worst leaving group
Aldehydes and ketones do NOT undergo nucleophilic acyl substitution

Question 14

Describe the mechanism of nucleophilic acyl substitution.

Answer 14

1) Addition of nucleophile to the carbonyl to give tetrahedral intermediate
2) Leaving group is then kicked out by the negative charge on the oxygen atom to reform the C=O bond

Question 15

Describe the mechanism of acyl chloride hydrolysis.

Answer 15

Water acts as a nucleophile - is added to the carbonyl, breaking one of the C=O bonds
Deprotonation then occurs, leaving an OH group and forming a tetrahedral intermediate
HCl is then removed, leaving a carboxylic acid

Question 16

What are the two mechanisms of ester hydrolysis?

Answer 16

Basic hydrolysis: nucleophile is deprotonated to make it more reactive
Acidic hydrolysis: The electrophile is protonated to make it more reactive

Question 17

Describe the mechanism of basic ester hydrolysis.

Answer 17

1) Nucleophilic addition of hydroxide
2) Elimination of alkoxide
3) Acid-base reaction
4) Protonation (acidic workup)

Produces a carboxylic acid and an alcohol
*Can use a variety of bases but NaOH is most common and acts as the nucleophile

Question 18

Describe the mechanism of acidic ester hydrolysis.

Answer 18

1) Protonation of ester
2) Nucleophilic addition of hydroxide
3) Acid-base reaction
4) Acid-base reaction 2
5) Elimination of alcohol
6) Acid-base reaction

Question 19

Describe the esterification reaction of carboxylic acids.

Answer 19

Based on the reverse of the acid hydrolysis as the steps are all reversible
Removing water and using an excess of alcohol to form the ester product

Question 20

Compare the hydrolysis of amides vs. esters.

Answer 20

Amides have stronger resonance stabilisation of the C-N bond compared to the C-O bond in esters
Amides require harsher conditions
Ester hydrolysis produces a carboxylic acid and alcohol, amide hydrolysis produces a carboxylic acid and an amine/ammonia

Question 21

Why do amides not readily undergo 1,2-additions?

Answer 21

Because the lone pair on nitrogen is good at stabilising partial positive charges on the carbon atom of the C=O bond
Makes it less available for nucleophilic attack and therefore less susceptible to addition reactions