Protecting Groups

Question 1

What is using a protecting group

Answer 1

1. Installing a functional group in a molecule temporarily to allow a particular reaction to be carried out
2. Then removing that group

Question 2

Why does ring opening of aziridine (when R group attached to N is H) need a protecting group

Answer 2

1. Organometals are basic and will deprotonate the NH instead of acting as a nucleophile

Question 3

What protecting groups can be used to protect an aziridine nitrogen prior to ring opening with a cuprate

Answer 3

1. Boc group

2. Sulfonamide

Question 4

What do you ideally want a protecting group to be if multiple are needed

Answer 4

1. Orthogonal

2. Each one to be removed under different reaction conditions than the others

Question 5

What is a downside to protecting groups

Answer 5

1. Adds at least 2 steps to the synthesis

2. unlikely to have yields of 100% so reduce overall yield for the synthesis

Question 6

What is the most common way to protect alcohols

Answer 6

1. Use of silyl ethers

Question 7

How do you form silyl ethers

Answer 7

1. Formed from the alcohols by using the corresponding silyl chloride
2. Add base and remove HCl (pyridine and imidazole often used)
3. No longer have acidic proton

Question 8

What changes the stability of a silyl ether

Answer 8

1. The more steric bulk around silicon the more stable the silyl ether
2. And the harder to remove

Question 9

How are Silyl ethers removed

Answer 9

1. By treatment with acid or with a source of fluoride (Si-F) is a very strong bond

Question 10

What are 4 sources of fluoride and describe properties of them

Answer 10

1. Hydrofluoric acid- most effective but can be too strong
2. Pyridine-HF complex
3. Triethylamine trihydrofluoride
4. Tetrabutylammonium fluoride- organic soluble because of non polar chains

Question 11

What are some problems with hydrofluoric acid

Answer 11

1. Extremely toxic and corrosive
2. Weaker acid
3. Water soluble and soluble in biological things e.g. skin
4. Calcium in bones reacts with F and dissolves them
5. Also attacks glass- use plastic

Question 12

How can the different stabilities of silyl ethers help

Answer 12

1. Can use several different silyl ethers in the same molecule and remove them selectively

Question 13

What is a different protecting group for alcohols

Answer 13

1. Use of tetrahydropyranyl ether (THP ether)

Question 14

How are THP ethers installed and removed

Answer 14

1. Under acid catalysis and removed the same way

2. Equilibrium

Question 15

What is a use of THP

Answer 15

1. Can be cleaved by acid but no by fluoride so can be seen as orthogonal to silyl ethers

Question 16

What is the common way to protect and aldehyde and ketone

Answer 16

1. Acetal or ketal

Question 17

How are acetals and ketal formed

Answer 17

1. By treating the carbonyl in question with a diol and catalytic acid
2. In equilibrium so important to remove the water with a Dean-Stark trap to drive the equilibrium to the right

Question 18

How do you remove acetal and ketal protecting groups

Answer 18

1. Deliberately add lots of water

Question 19

What else can the acetal/ketal reaction be used for

Answer 19

1. Can be used to protect a diol- add an aldehyde or ketone

Question 20

What a major use of protecting groups

Answer 20

1. Can be used to make Grignard reagents that would not be accessible otherwise
2. e.g. might one with a carbonyl group might react with itself
3. So use ketal protecting group so ketone carbon is no longer electrophilic

Question 21

How can protecting groups be used to allow access to Grignard containing alchols

Answer 21

1. Grignard reagents are strong bases as well as strong nucleophile and the OH contains an acidic proton
2. So it would deprotonate itself
3. So protecting group can add to alcohol so it can act as a nucleophile and then is removed at the end