Amide And Peptide Synthesis Flashcards
Why can ammonia not simply be added to a carboxylic acid to form an amide?
Because OH is a bad leaving group
What is required to form a basic amide?
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
What drives the reaction to form an amide?
The reaction is driven by the formation of a stable amide bond - since it has partial double bond character
Why use p-nitrophenol in amide synthesis?
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
What is DCC and what is its function in amide synthesis?
DCC = Dicyclohexyl carbodiimide
It allows good leaving groups (or amines) to replace the OH group.
KNOW MECHANISM
Why are amide N not basic?
Because N lone pair is not available for protonation - delocalised in carbonyl
What is GABA?
A neurotransmitter, controlling nerve impulses
What is Monodosodium glutamate?
‘Meaty’ floured food additive
What is aspartame?
Artificial sweetener - 1000x sweeter than sugar
What is TRH?
It’s a hormone which controls release of thyrotrophin in the body
What are enkephalins?
They’re peptides that are involved in the sensation of pain
Have 5 peptide residues
What is angiotensin 2?
It’s used in the body to increase blood pressure, it’s a hypertensive agent.
It has 8 peptide residues
What is cyclosporin A?
It is a cyclic peptide that is used to treat organ rejection after implants
It has 10 peptide residues
Why are protecting groups required in peptide synthesis?
Because two different peptides can form
Amine of AA1 can attack acid of AA2 - and vice versa
What is a protecting group?
It’s a group that blocks or suppresses the reactivity of a reactive functional group
Achieved either terminally or electronically
What properties must protecting groups have to be of synthetic use?
Must be added/removed in high yield
Must be stable to subsequent reactions
What’re the 3 most commonly used protecting groups for amide synthesis?
Z-chloride
BOC (anhydride)
FMOC (chloride)
Whats the structure of Z-chloride?
What’s the structure of BOC (anhydride)?
t-butyloxycarbonyl
What’s the structure of FMOC (chloride)?
Structure is commonly abbreviated to FMOC due to its size and complexity
How is the FMOC protecting group removed?
With piperidine
How are Z-protecting groups removed?
Using H2 on Pd
Selectively reduces amide to amine
What is the sequence required to bind AA1 to AA2?
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
How are carboxylic acids protected in amide synthesis?
Using MeOH/HCl or t-BuOH/HCl
How can protected carboxylic acids be returned to normal?
They can be hydrolysed using basic catalysis
Eg. LiOH
What is DIBAL? What is its structure?
It is a source of hydride, H-
Whats the use of DIBAL?
Reduces ester to a primary alcohol at low temperatures
Whats the use of PCC or PDC?
They oxidise primary alcohols to aldehydes/ketones
Of the protecting groups used for amide synthesis, which are solution phase only?
Z-protecting groups
Of the protecting groups used for amide synthesis, which can be used in solid or solution phase?
FMOC and BOC
