Amide And Peptide Synthesis

Question 1

Why can ammonia not simply be added to a carboxylic acid to form an amide?

Answer 1

Because OH is a bad leaving group

Question 2

What is required to form a basic amide?

Answer 2

PCl5 is added to a carboxylic acid - forming an acid chloride

Desired amine can then be added and Cl- leaves - forming desired amide.

KNOW MECHANISM

Question 3

What drives the reaction to form an amide?

Answer 3

The reaction is driven by the formation of a stable amide bond - since it has partial double bond character

Question 4

Why use p-nitrophenol in amide synthesis?

Answer 4

It replaces the OH of the carboxylic acid

P-nitrophenol is a good leaving group and is a highly stable anion when kicked off in the final step of amide synthesis

Question 5

What is DCC and what is its function in amide synthesis?

Answer 5

DCC = Dicyclohexyl carbodiimide

It allows good leaving groups (or amines) to replace the OH group.

KNOW MECHANISM

Question 6

Why are amide N not basic?

Answer 6

Because N lone pair is not available for protonation - delocalised in carbonyl

Question 7

What is GABA?

Answer 7

A neurotransmitter, controlling nerve impulses

Question 8

What is Monodosodium glutamate?

Answer 8

‘Meaty’ floured food additive

Question 9

What is aspartame?

Answer 9

Artificial sweetener - 1000x sweeter than sugar

Question 10

What is TRH?

Answer 10

It’s a hormone which controls release of thyrotrophin in the body

Question 11

What are enkephalins?

Answer 11

They’re peptides that are involved in the sensation of pain

Have 5 peptide residues

Question 12

What is angiotensin 2?

Answer 12

It’s used in the body to increase blood pressure, it’s a hypertensive agent.

It has 8 peptide residues

Question 13

What is cyclosporin A?

Answer 13

It is a cyclic peptide that is used to treat organ rejection after implants

It has 10 peptide residues

Question 14

Why are protecting groups required in peptide synthesis?

Answer 14

Because two different peptides can form

Amine of AA1 can attack acid of AA2 - and vice versa

Question 15

What is a protecting group?

Answer 15

It’s a group that blocks or suppresses the reactivity of a reactive functional group

Achieved either terminally or electronically

Question 16

What properties must protecting groups have to be of synthetic use?

Answer 16

Must be added/removed in high yield

Must be stable to subsequent reactions

Question 17

What’re the 3 most commonly used protecting groups for amide synthesis?

Answer 17

Z-chloride

BOC (anhydride)

FMOC (chloride)

Question 18

Whats the structure of Z-chloride?

Answer 18

Question 19

What’s the structure of BOC (anhydride)?

Answer 19

t-butyloxycarbonyl

Question 20

What’s the structure of FMOC (chloride)?

Answer 20

Structure is commonly abbreviated to FMOC due to its size and complexity

Question 21

How is the FMOC protecting group removed?

Answer 21

With piperidine

Question 22

How are Z-protecting groups removed?

Answer 22

Using H2 on Pd

Selectively reduces amide to amine

Question 23

What is the sequence required to bind AA1 to AA2?

Answer 23

Protect AA1 amino acid with FMOC or Z
Activate COOH of AA1 - convert OH to good LG

Protect COOH of AA2
Then react amine of AA2 with activated ester of AA1 to form amide bond

Then remove protecting group (Z) and hydrolyse ester to give product

Question 24

How are carboxylic acids protected in amide synthesis?

Answer 24

Using MeOH/HCl or t-BuOH/HCl

Question 25

How can protected carboxylic acids be returned to normal?

Answer 25

They can be hydrolysed using basic catalysis

Eg. LiOH

Question 26

What is DIBAL? What is its structure?

Answer 26

It is a source of hydride, H-

Question 27

Whats the use of DIBAL?

Answer 27

Reduces ester to a primary alcohol at low temperatures

Question 28

Whats the use of PCC or PDC?

Answer 28

They oxidise primary alcohols to aldehydes/ketones

Question 29

Of the protecting groups used for amide synthesis, which are solution phase only?

Answer 29

Z-protecting groups

Question 30

Of the protecting groups used for amide synthesis, which can be used in solid or solution phase?

Answer 30

FMOC and BOC