Chapter 20 Enolates / other Carbanions

C-C bond formation is very important⇒ larger more complex organic molecule can be made from⇒ larger, more complex organic molecule can be made from smaller ones

How?

carbon nucleophile + carbon electrophile

⇒C C C C

Carbon electrophile orO

δ+ δ-Carbon electrophile: or R X

R C Aδ+ δ-

δ+⇒ abundant

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How about carbon nucloephile?li it d⇒ limited

Ex) cyanide ion: M+ -CN

acetylide ion:

ylide:

Grignard reagent and organo metallic compound:

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R-X + 2Li → RLi + LiX

⇒ Grignard reagent and organometallic compund are not useful for SN2 reactions because they are too reactive.

For the SFor the SNN2 enolates are used2 enolates are usedBecause they are not as reactive as organometallicBecause they are not as reactive as organometallic compunds, then C-C bond through SN2 can be formed

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20.1 Enols and Enolate Anions

⇒ both are possible under acidic and basic conditions

In acidic condition

In basic condition

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Equilibrium constants of carbonyl and enol tautomers for base condition

Highe

diketo er value f

one > ket for

1,

3

toester > -dicarbo

> diester onyl com

r

mpounds

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s

What kinds of base can we use?

R CO

CHbase

R CO

CH R' + BHR C CH2 R' B R C CH R' + BH

R'' XR -X

R CO

CH R'R C CH R

Use base whose pKas of conjugate acids are greater

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than those of the carbonyl base !

For

Use compunds whose pKas of conjugate acids are greater than 30 such assuch as

For

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Ethoxide can be used (pKa ~ 16)

20.2 Halogenation of the α-CarbonThe reaction of an aldehyde or ketone with Cl2, Br2, or I2 under either acid or basic conditionor I2, under either acid or basic condition

Both acidic and basis conditions can be usedBoth acidic and basis conditions can be used

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Under acidic conditions

The presence of the halogens retards the enolation, so the addition of single halogen is possibleg g p

Examples

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Under basic conditions

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Example

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20.3 Alkylation of Enolate Anions

⇒ Enolates from esters, ketones, and nitriles can be used in SN2 reactions (alkylations).can be used in SN2 reactions (alkylations).

Ex)

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⇒ Aldehydes cannot be used in such reactions⇒ Aldehydes cannot be used in such reactions because they are too reactive (side reactions)

1 Reactions with base1. Reactions with base

R CO

HR C H

BNo steric hidrance !

2. Reactions with themselves: Aldol condensation

(later)(later)

LDA: lithium diisopropylamideLDA: lithium diisopropylamide

⇒ It is a very strong base but not very nucleophilic due to the steric hindrance

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nucleophilic due to the steric hindrance

To avoid the formation of two products, deprotonation of the ketones must produce a single enolate ionthe ketones must produce a single enolate ion.

Examples

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20.4 Alkylation of More Stabilized Anions

Strong nucleophiles are normally strong bases,Strong nucleophiles are normally strong bases, then many side reactions are possible.

1.Elimination

2.Unwanted substitution2.Unwanted substitution

O O R-XH3C C CHR' R C CH2 R'

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Therefore we might need to use less nucleophilic

enolates,

Then we might need more steps to, still the yieldThen we might need more steps to, still the yield

can be higher due to less side reaction.

ExampleCh 10.2

Ch 10.6

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Ch 10 2Ch 10.2

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Ch 10.6

Why?

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This time, ethyl acetoacetate can be used instead of acetone!

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Mechanism

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Example

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Diethyl malonate can be used instead of acetic acid

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Preparation of substituted β-ketoesters, β-diester, and dinitrile ⇒ without hydrolysis

Next page

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20.5 The Aldol Condensation

(aldehyde + base) cannot be used for the alkylation ( y ) yof alkyl halide, because of the aldol condensation!

Carbonyl carbon of aldehyde is much moreCarbonyl carbon of aldehyde is much more electrophilic than those of ester, ketone, and nitrile!

ester ketone and nitrile ⇒ S 2

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ester, ketone, and nitrile ⇒ SN2

<Mechanism>

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If the aldol condensation is conducted under very vigorous conditions (higher temperature, longer reaction time, and/or strong base

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<Examples><Examples>

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K tKetonesAs less electrophilic, usually no aldol condensation.

However when the product is 5- or 6- membered ring, then aldol condensation occurs!aldol condensation occurs!

<Example>

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Mixed aldol condensationMixed aldol condensation

4 products =

2 acidic compounds x 2 electrophilic compounds

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Use aromatic aldehyde (only electrophilic) y ( y p )to get one product. Product is more favorable: conjugationProduct is more favorable: conjugation

<Example><Example>

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<Examples>

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20.6 Ester Condensation20.3-4: enolates with alkyl halide using weak or strong bases depending on the acidity.

R CO

CH2 R'base

B R CO

CH R' + BH2 B

R''-X

OR C

OCH R'R''

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20.5: enolate with aldehyde using weaker bases. ⇒

20 6: enolate with ester using weaker bases ⇒

Aldol condensation

20.6: enolate with ester using weaker bases. ⇒Ester condensation or Claisen ester condensation

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Mechanism of the Claisen Ester Condensation

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For the compounds with only one on the α-carbon, Step 4 is impossible.

Th th t d ti i i iblThen the ester condensation is impossible

If stronger base is used, then condensation is possible

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Dieckmann condensatoin⇒ Intramolecular ester condensation

Mixed ester condensation can be prevented if one of the component acts as only electrophile such ascomponent acts as only electrophile such as

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<Examples>

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20.7 Carbon and hydrogen leaving groups

A carbanion as a leaving group

Haloform reaction

Adol condensation

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A hydride as a leaving group, Cannizzaro reactionCannizzaro reaction

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Cannizzaro reaction

example

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20.8 Enamines

The enamine can be used as a carbon nucleophile !The enamine can be used as a carbon nucleophile !

In ch 18.8

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α-carbon is nucleophilic, still weaker nucleophile than the enolates. Therefore for SN2 reaction, the alkyl halide must be very reactive such as:

<Examples>

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<Examples><Examples>

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20.9 Other Carbon Nucleophiles

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Example reactionExample reaction

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E ample reactionExample reaction

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Other Carbon Nucleophiles

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Using two equivalent of LDA

more nucleophic site is reactedmore nucleophic site is reacted

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20.10 Conjugated Addition

O1,2 addition: Grignard reagent, hydride

CCH2

1,2 addition: Grignard reagent, hydride

→ stronger nucleophile2

1 2 addition1,4 addition: cyanide, amine

l ti l hil

1 4 addition

1,2 addition → less reactive nucleophile

or sterically hindered1,4 addition See CH 18.10

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In CH 20 Michael reaction→ enolate and related carbanion

++

α,β-unsaturated carbonyl compound

In Michael reaction only catalytic amount of base is needed

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Michael reaction mechanism

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Examples of Michael reaction

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Robinson annulation⇒ Michael reaction + aldol condensation

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20.11 Synthesis

Retrosynthetic Arrow

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Other example

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SummarySummary

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