Carbonyl chemistry- Nitrogen nucleophiles with aldehydes and ketones

Question 1

What happens if you add a diamine to an aldehyde/ketone

Answer 1

1. It forms a group analogous to acetals

2. It is easy to form but hard to remove so difficult to use as a protecting group

Question 2

How can you form an imine

Answer 2

1. When primary amines react with an aldehyde or ketone
2. Use aqueous acid catalyst
3. Reversible reaction
4. Water is formed which needs to be removed from reaction by molecular sieve, MgSO4 or Dean Stark

Question 3

How can you hydrolyse an imine

Answer 3

1. Add Water and acid

2. Not all imines hydrolyse the same, some are much more stable to H+ hydrolysis

Question 4

What is the pH needs in the formation of an imine from aldehyde/ketone

Answer 4

1. pH 4-6
2. First part of reaction can’t be too acidic as the amine would be protonated before it attacks the aldehyde. pH below 4 inhibits attack
3. Second part of reaction requires acidic pH to allow protonation of OH- pH above 6 inhibits protonation

Question 5

Compare the formation of imine to acetyal

Answer 5

1. Oxonium formed first as need to make aldehyde as reactive as possible as poor nucleophile (alcohol)
2. This is not needed in imine formation as better nucleophile (amine)
3. Acetal does not require extra acid but it is need in imine to protonate

Question 6

What happens when a secondary amine is reacted with an aldehyde or ketone

Answer 6

1. Gives an enamine

Question 7

What are imines and enamines chemistry comparable to

Answer 7

1. Imines- ketones and aldehydes

2. Enamine- enols

Question 8

What is required to form an enamine from a ketone

Answer 8

1. secondary amine
2. Dean stark
3. toluene
4. H+ pH 4-6

Question 9

What is formed if there is an unsymmetrical ketone reacting with the amine

Answer 9

1. Always form enamine that is least substituted- sterics

Question 10

Describe reactivity of imine

Answer 10

1. Has lone pair on N so can act as Lewis base
2. Delta +ve carbon which can be attacked by nucleophiles
3. Alpha proton which is acidic and can be deprotonated
4. Behaves in exactly the same way as aldehyde or ketone

Question 11

Describe reactivity enamine

Answer 11

1. Both the N and C not adjacent to N are delta -ve, so electrophiles have 2 sites of attack.
2. They always react at C atom though as it is…HOMO
3. Behaves like enol of aldehyde or ketone

Question 12

What reactions do imines typically undergo

Answer 12

1. Nucleophilic addition

Question 13

What reactions do enamines typically undergo

Answer 13

1. Electrophilic addition + removal of N which is replaced by C=O

Question 14

What is formed in these reactions:

1. Ketone + primary amine
2. Ketone + secondary amine
3. Aldehyde + secondary amine

Answer 14

1. Imine
2. Enamine
3. Iminium ion

Question 15

What is the best way to make secondary amines

Answer 15

1. Reductive amination

2. From a ketone/aldehyde

Question 16

Describe what is needed in reductive amination

Answer 16

1. Need a mild hydride source- has to be a selective reducing reagent
2. pH around 4-6- same reasons as for formation of imine
3. Add primary amine

Question 17

What is a good reducing agent for reductive amination

Answer 17

1. If too strong- would reduce aldehyde to alcohol before amine was involved
2. NaBH3CN- won’t reduce aldehydes/ketones- only reduces the high energy intermediate- iminium ion

Question 18

What are iminium ions useful for

Answer 18

1. Synthesising amino acids

2. Useful if unnatural amino acids are required

Question 19

Describe the steps for synthesising an amino acid using iminium ions

Answer 19

1. First form iminium using NH4Cl to form NH2 + OH group on carbonyl carbon
2. Form iminium ion
3. CN attacks the ion
4. NH2 + CN groups attach to the former carbonyl carbon
5. Add H+ (aq) CN hydrolyses to forms carboxylic acid group