Carbonyl chemistry- alkylation of enolates

Question 1

Describe the conditions which cause reaction at oxygen of enolate

Answer 1

1. Hard electrophiles
2. Polar aprotic solvents (DMSO, DMF)
3. Large enolate counter ion- not so tightly bound so more naked

Question 2

Describe the conditions which cause reaction at carbon of enolate

Answer 2

1. Soft electrophiles

2. Ethereal solvents (THF, Et2)

Question 3

How can you alkylate a ketone

Answer 3

1. Form an enolate by addition of base

2. Alkylate using R-X

Question 4

What type of bases can you use and what effect do they have

Answer 4

1. Strong base- add base first then electrophile

2. Weak base- add base and electrophile at same time

Question 5

Why are the electrophile and base added at the same time for when weak bases are used to alkylate

Answer 5

1. Only little bits of enolate form at a time so need to add electrophile at same time to catch enolate as fast as you can

Question 6

What is a common side reaction and when is this an issue

Answer 6

1. Multiple alkylation is a common side reaction

2. Issue if excess of bae is employed

Question 7

What can be alpha-alkylated

Answer 7

1. Generally, if you have alpha-protons which are acidic

2. Specific enol equivalents- enol ethers, silyl enol ethers and enamines

Question 8

What is formed when enamines react with akylating agents

Answer 8

1. Final compound is the corresponding ketone not the enamine

Question 9

What is formed when silyl enol ethers react with alkylating agents

Answer 9

1. Corresponding ketone not the silyl enol ether

Question 10

What alkylating agent is used for silyl enol ethers and how are they prepared

Answer 10

1. Tertiary alkyl halides

2. Needs to form a carbocation by reaction with Lewis acid- removes halide

Question 11

How else can ketones be alkylated

Answer 11

1. Using non-nucleophilic bases to form enolates (LDA)
2. E.g lithium enolate
3. Then add alkyl halide

Question 12

Why can’t aldehydes be alkylated using lithium enolates

Answer 12

1. They are too reactive

2. If lithium enolate formed it will quickly self condense

Question 13

How can esters be alkylated

Answer 13

1. Have alpha protons which are acidic
2. Can react with their own enolate- Claisen Condensation
3. Need to convert to enolate and keep cold to prevent side reaction

Question 14

How can carboxylic acids be alkylated

Answer 14

1. Acid proton of OH will react first with any base
2. Once H has been removed nucleophilic bases can be used and a Iwanow intermediate is formed
3. Then the electrophile and H+ is added

Question 15

What can alpha, beta unsaturated carbonyls act as

Answer 15

1. Electrophiles for soft nucleophiles e.g. organo copper/cuprates- Me-Cu
2. Can be alkylated by the Me and Cu leaves
3. Need soft nucleophile to react at beta carbon

Question 16

Where do different carbonyl derivatives react in conjugate addition

Answer 16

1. Acyl chlorides and more reactive carbonyls always react at C=O
2. amines- react at beta carbon
3. Ones in the middle react with either

Question 17

What problems do you get with ketone reduction with hydride sources E.g. NaBH4, EtOH

Answer 17

1. Regiochemistry issues- may reduce at C=C or C=O or both

2. Can’t control

Question 18

How can the reduction of enones be forced at C=O

Answer 18

1. Using CeCl3

2. Luche reduction

Question 19

How can conditions for alpha,beta-unsaturated carbonyls enolate alkylation be used to promote 1,4/Michael addition not 1,2

Answer 19

1. Form either Na/K enolates- enamine, silyl enol ether

2. Use stabilised enolates e.g. where they can form hydrogen bonding 6 membered ring

Question 20

How does enolate addition to carbonyls work in Michael addition

Answer 20

1. The beta double bond breaks and attaches to the carbonyl species where the acidic proton is

Question 21

What reduces the pKa of the alpha-proton

Answer 21

1. The presence of additional electron withdrawing group alpha to the carbonyl
2. e.g. COR, CO2R, CN etc

Question 22

What group particularly is important in reducing acidity of alpha-proton

Answer 22

1. 1,3-dicarbonyls
2. Malonate- double ester
3. B-keto-ester

Question 23

What is the significance of having a low pKa of the alpha hydrogen

Answer 23

1. Can now be deprotonated by weak bases e.g. CO32-

Question 24

What else can happen to 1,3-dicarbonyls

Answer 24

1. They can be decarboxylated

Question 25

Describe how 1,3-dicarbonyls can be decarboxylated e.g. double ester

Answer 25

1. First a base is used to hydrolyse both esters
2. Forms a double carboxylate intermediate
3. Then an acid is added to protonate O-
4. Heat added allows CO2 group to be removed and double bond with two alcohols is left
5. This can be tautomerised to produce carboxylic acid