4a: Enolates

Question 1

What are the pK_as of water, propanone, LDA and acetic acid?

Answer 1

Water = 14

Propanone = 20

LDA = 35

Acetic acid = 5

Question 2

Why does the base have to be 5 pK_a higher than the target for full deprotonation?

Answer 2

So in the equlibrium for protonated:deprotonated, deprotonated is 5x larger than protonated and self condensation reactions aren’t favoured.

Question 3

How do you produce LDA?

Answer 3

Diisopropylamine with BuLi in THF at 0°

Question 4

Are enolates hard or soft? What 3 alternatives can be used in replacement and how do you use them?

Answer 4

Hard, soft alternatives include:

• β-keto ester, use sodium base to match ester, ester removed by 1. NaOH 2. HCl and heat.
• Silyl enol ether (O-SiMe₃), use NEt₃ to deprotonate, use for aldehydes as LDA can’t be used, formed from ClSiMe₃, activate using MeLi for reactions as an enolate and TiCl₄ to make carbonyls more electrophilic to react 1,4.
• Enamines, formed using pyrrolidine, p-TsOH and MgSO₄, removed by HCl, works with aldehydes, at room temp and is stable. They can’t be used for esters and have complexities with ketones.

Question 5

What is the mechanism for the ester removal from a beta keto ester?

Answer 5

Question 6

How do you form a silyl enol ether?

Answer 6

The carbonyl reacts with ClSiMe₃ to form a carbocation. Then NEt₃ removes a hydrogen to form the enolate equivalent.

Question 7

Draw 2 mechanisms for the 2 activations of silyl enol ethers.

Answer 7

Question 8

Draw a mechanism for the formation and removal of an enamine.

Answer 8

Question 9

What do you have to think about when deprotonating ketones and when using enamines?

Answer 9

Ketones: 1. Kinetic control - the quickest place to deprotonate favoured with the least steric hinderence. 2. Thermodynamic control - most stable position favoured (most substituted alkene formed)

Enamines are large and can have steric clashes with their hydrogens stopping them form the most stable products. They also will form structures with conjugation when they have the option.

Question 10

If you have a dicarbonyl, how do you react from the harder site to deprotonate?

Answer 10

By using the dianion trick, deprotonate with a weaker base such as NaOEt, then deprotonate the harder position with LDA or BuLi. The harder position to deprotonate will be the first to react.

Question 11

How can you avoid use of LDA?

Answer 11

Alternative enolates such as enamines and good electrophiles such as acyl chlorides.

Question 12

How can cyclic compounds be made easily?

Answer 12

Using a self condenstion on a dicarbonyl.

Question 13

List each type of common carbonyl and suitble reagents for reactions as enolates.

Answer 13

Aldehydes: Silyl enol ethers (with activation)/enamines

Ketones: LDA/enamine (consider regiochemistry)

Esters: LDA

Question 14

List nucleophiles that attack by 1,2 addition.

Answer 14

H^- (LiAlH₄), R^- (RMgBr = RBr + Mg), Me^- (MeLi = MeBr + 2Li)

Question 15

List nucleophiles that attack by 1,4 addition.

Answer 15

Me^- (Me₂CuLi(stronger and harder)/MeCu = CuI + 1/2MeLi), Enolate (silyl enol ether, enamine, beta keto ester), carboxyl (beta diester)

Question 16

What are the protecting groups for alcohols, carboxylic acids and ketones/aldehydes?

Answer 16

Alcohols: R-OTBDMS

Carboxylic acids: Esters

Ketones/aldehydes: Acetals