Enolates

Question 1

How are enolates normally generated

Answer 1

1. Deprotonation of the corresponding carbonyl

Question 2

What is important to achieve a high concentration of desired enolate

Answer 2

1. Correct selection of the base

2. Need the substrate to be substantially more acidic than the conjugate acid

Question 3

List typical groups of bases

Answer 3

1. Alkoxides (usually with Na as counterion)
2. Alkali metal hydrides
3. Alkali metal amides

Question 4

Name two alkali metal hydrides

Answer 4

1. NaH

2. KH

Question 5

Name two alkali metal amides

Answer 5

1. NaH2

2. KNH2

Question 6

What are some particularly useful amides and why

Answer 6

1. Those derived from deprotonation of secondary amines
2. LDA and LHMDS
3. These are soluble in inert solvents such as THF
4. and are hindered and therefore non-nucleophilic strong bases

Question 7

Describe alkyllithiums

Answer 7

1. Very strong bases

2. Not often used for enolate formation as are also good nucleophiles, which leads to side reactions

Question 8

What is the pka for a tertiary amide

Answer 8

1. 30

Question 9

What is the pka for an ester

Answer 9

1. 24.5

Question 10

What is the pka for a ketone

Answer 10

1. 19-20

Question 11

What is the pka for an aldehyde

Answer 11

1. 17

Question 12

What is the pka for a malonate

Answer 12

1. 13

2. (a beta-diester)

Question 13

What is the pka for a beta-ketoester

Answer 13

1. 11

Question 14

What is the pka for a beta-diketone

Answer 14

1. 9

Question 15

What else does the rate of alkylation of enolates depend on

Answer 15

1. Very solvent dependent

Question 16

Give 3 examples of polar aprotic solvents

Answer 16

1. DMF, DMSO, HMPA

Question 17

Describe polar aprotic solvents with enolates

Answer 17

1. Good cation solvators

2. Leave a naked, reactive anion

Question 18

Give 2 examples of weakly polar solvents

Answer 18

1. THF, DME

Question 19

Describe weakly polar solvents with enolates

Answer 19

1. Still able to coordinate cations but with a smaller charge separation
2. Generating less reactive enolates

Question 20

What is an issue with enolate alkylation

Answer 20

1. Issue of C vs O alkylation

Question 21

When is it more likely to be C alkylation

Answer 21

1. Small cations such as Li+ bind tightly to oxygen promoting C-alkylation
2. Halides favour C-alkylation

Question 22

When is it more likely to be O-alkylation

Answer 22

1. Larger cations such as K+ favour O-alkylation

2. Oxygen derived leaving groups promote O-alkylation

Question 23

What is OTs

Answer 23

1. para-toluenesulfonate or tosylate

2. Sulfonates are leaving groups that can be synthesised in 1 step from the corresponding alcohol

Question 24

How do you form a tosylate

Answer 24

1. From the corresponding alcohol
2. Add ClSO2(benzene to methyl)
3. • NEt3, -Et3NH+ Cl-
4. R group attaches to O

Question 25

What is the difference between the kinetic and thermodynamic enolate

Answer 25

1. Kinetic enolate- fastest forming enolate, removal of least hindered proton
2. Thermodynamic enolate- more stable, more substituted enolate

Question 26

What conditions favour the kinetic enolate

Answer 26

1. Excess of a strong hindered base (LDA)

2. at low temperature -78 degrees

Question 27

What conditions favour the thermodynamic enolate

Answer 27

1. Adding a strong base (KOtBu)to the ketone

2. Room temperature or above

Question 28

What can you do with a mixture of kinetic and thermodynamic enolates

Answer 28

1. Can be trapped as stable derivatives and then separated

2. Prepare silyl enol ethers

Question 29

How can you prepare silyl enol ethers

Answer 29

1. Trapping the enolate mixture with a trialkyl silyl chloride
2. Most common TMS-Cl

Question 30

What do you do when you have produced two different silyl enol ethers

Answer 30

1. Isolate and separate by distillation

2. Then treatment with methyl lithium regenerates the enolate

Question 31

What is an alternative method to achieve deprotonation at a specific position

Answer 31

1. Introduce an activating group that increases the acidity of the desired proton
2. Usually achieved by the introduction of a further EWG e.g. ester
3. After alkylation the activating group can be removed by hydrolysis and then decarboxylation

Question 32

What are some problems with direct alkylation of ketones

Answer 32

1. Double alkylation

2. Self condensation

Question 33

What is a solution to the problems of direct alkylation of ketones

Answer 33

1. Use enamines

Question 34

How do you form an enamine

Answer 34

1. By reaction of a secondary amine with a carbonyl compound
2. In presence of an acid catalyst

Question 35

What are the most commonly used amines

Answer 35

1. Pyrrolidine

2. morpholine

Question 36

Are enamines nucleophilic or electrophilic

Answer 36

1. Nucleophilic at the beta-position

Question 37

What are advantages to using enamines

Answer 37

1. No base is used- no self condensation occurs
2. Monoalkylation is usually observed (intermediate mono-alkylenamines are unreactive towards further reaction)
3. Alkylation of unsymmetrical ketones is regioselective; the major enamine is the less substituted (steric inhibition of resonance)

Question 38

What do you have to use to drive formation of an enamine

Answer 38

1. Dean-Stark Trap

2. Removes water to drive forward reaction

Question 39

Where does deprotonation take place in an alpha,beta-unsaturated ketone under kinetic conditions and therefore where can alkylation take place

Answer 39

1. At alpha’ carbon

2. Kinetic enolate- O or C alkylation