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Lecture 2 Flashcards

1
Q

What is the carbonyl reactivity series

A
  1. Acyl halide> anhydride» ester = acid&raquo_space; amide
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2
Q

What happens if we mix a carboxylic acid and an amine together to get them to react

A
  1. Nothing much, they form the salts as the amine will deprotonate the acid and neither is reactive
  2. Need to make the acyl halide or anhydride to give RCOX, where X is the better leaving group
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3
Q

How can you make acid chlorides

A
  1. Carboxylic acid + thionyl chloride –> Acid chloride + SO2 + HCl
  2. Carboxylic acid + oxalyl chloride –> Acid chloride + CO2 + CO + HCl
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4
Q

What is problem with thionyl chloride route to making acid chlorides

A
  1. Conditions are quite harsh (refluxing in SOCl2)
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5
Q

Describe the reaction of an acyl chloride with an amine

A
  1. Pyridine + acyl chloride + amine –> amide + pyridine (catalyst)
  2. Can get racemisation via ketene formation and then addition of amine - but not a lot of ketene so not fully racemic mixture
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6
Q

What is the role of pyridine and DMAP in the reaction of acyl chlorides and amine

A
  1. Used as a catalytic nucleophile as well as a base in the reaction
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7
Q

How can you form an acid fluoride

A
  1. Carboxylic acid + cyclic N thing with 3 F substituents + pyridine
  2. Produced an activated ester which then produces an acid fluoride
  3. Can be useful in some conditions
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8
Q

How can carbodiimides be used to produce amides

A
  1. carboxylic acid + amine to produce salts
  2. Then add carbodiimide (DCC) e.g. diisopropyl to produce o-acylurea which reacts with amine
  3. Produces amide and urea
  4. Activating group for an acid so no need to make a acid chloride
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9
Q

What are problems of using carbodiimides to produce amides

A
  1. N-acylurea formation - side reaction - from migration - happens if amine is not strongly nucleophilic
  2. Racemisation
  3. Acyl migration - what happens above
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10
Q

Describe the racemisation that occurs when synthesising peptides using carbodiimides

A

1.Particular problem when synthesising from N- to C-terminus
2. Activating the terminal carboxylic acid can allow for attack by the penultimate carbonyl
3. As the ester is not reactive enough

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11
Q

What is driving force for synthesising peptides using carbodiimides

A
  1. Formation of very stable urea
    2.c=o is very strong and energetically favourable
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12
Q

How can you get around problem of racemisation and side reactions when forming a peptide without acid chloride

A
  1. Activate the ester
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13
Q

How can the DCC ester be activated

A
  1. Using a nucleophilic species e.g. R-OH
  2. Forms O-R bond in ester- very good leaving group
  3. HOBT and HOAT are most common
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14
Q

What is HOBt and HOAt

A
  1. Oxygen is next to another electronegative element e.g. N
  2. Alpha nucleophiles
  3. Makes very good nucleophiles
  4. HOAt has extra pyridyl nitrogen which can reduce racemisation
  5. HOBt is cheaper so more commonly used
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15
Q

What is an NHS-ester

A
  1. Activated ester
  2. Uses disuccininimyl carbonate
  3. Can be brought so useful - but expensive
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16
Q

What can be used instead of HOAt and HOBt

A
  1. Problem with them is 2-step process - first carbodiimide then add alphanucleophile to get activated ester
  2. Can use BOP and PyBOP instead
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17
Q

What is BOP an PyBOP

A

1.Phosphate species
2. Driving force is to generate phosphine oxide
3. Acts as combination of DCC and HOBt in one- one reaction
3. Containg HOBt

18
Q

What is problem with BOP

A
  1. Produces phosphine oxide (HMPA)
  2. Very mutagenic
19
Q

Why is PyBOP better

A
  1. Uses pyrrolidine instead of NMe2
  2. Less toxic as doesn’t produce HMPA
20
Q

What is another single reagent that can react with acid to generate activated ester

A
  1. HATU
  2. Similar to BOP etc
  3. Doesn’t need DCC as well
  4. Contains HOAt instead of HOBt
21
Q

Describe how HATU works

A
  1. Base deprotonates the carboxylic acid
  2. Resultign carboxylate anion attacks the electron deficient carbon atom of HATU
  3. Resulting HOAt anion reacts with the newly formed activated carboxylic acid derived intermediate to form an OAt activated ester
22
Q

Which method for producing amide is most commonly used

A
  1. HOAt and HOBt are used first as cheap
  2. Then move on to other methods if unsuccessful
23
Q

What carbodiimides can be used

A
  1. DCC - two cyclohexanes attached
  2. DIC- CH(CH3)2 attached
  3. EDC/EDCl- resulting urea is water soluble - eliminated by water washes
24
Q

How do you remove waste at end of forming amide with DCC

A
  1. Resulting urea is poorly soluble
  2. Removed by filtration
  3. Solution-phase chemistry
25
What is the problem with the formation of amide
1. Problem with selectivity making amide bond 2. Reactants react with themselves
26
How can you resolve the problem of reactants reacting with themselves
1. Need to introduce protecting groups to protect the functionality in the molecule to stop a reaction occurring at that point
27
What were the original protecting groups
1. Ester for carboxyl group 2. N-benzyl protection for the amino group 3. Forms dipeptide then need to remove protecting group to create longer peptide 4. OMe group is stable in conditions required to remove N-benzyl
28
How can you add methoxy ester to a carboxylic acid and what is point
1. Methoxy ester protects carboxylic acids using methanol and HCl
29
How is methoxy ester removed to produce acid
1. Using NaOH/ MeOH or H2O 2. Depends on solubility
30
What are some of the best protecting groups
1. Boc - protect amines and alcohols 2. Fmoc - protects amine group 3. Methoxy ester - protects carboxylic acids
31
Describe benzyl as a protecting group
1. Attached using benzyl bromide 2. removed using hydrogenation H2 3. Very bulky but nice to remove 4. Protect amines
32
What is Boc
1. Comes from tertiary butyloxycarbonyl (Boc) groups 2. Protect amines and alcohols 3. O=C-O-C-(CH3)3
33
How is Boc added to act as a PG
1. Using Boc anhydride and base
34
How is Boc removed
1. Using acid 2. TFA or 3M HCl
35
When is Boc not popular
1. Uses acid to remove- sometimes not good
36
What is used if removal of Boc by acid is not watned
1. Fmoc- removed by a base
37
Describe Fmoc
1. 9-Fluorenylmethyloxycarbonyl 2. Protects amine gorups
38
How is Fmoc added to a amine
1. Reaction with Fmoc-Cl or Fmoc-succinimde produces HCl
39
How is Fmoc removed
1. By exposure to piperidine (base) 2. Due to the acidic fluorenyl proton
40
Why can Fmoc be removed by a base
1. fluorenyl proton is acidic 2. Aromatic so stable carbanion
41
Why are other protecting groups required
1. Selectivity 2. Stability to reaction conditions 3. Stability to deprotection conditions 4. Other groups in the molecule- amino acids have other groups like phenol 5. Orthogonality

aa Biomolecules (9 decks)

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