Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using...

65
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 or O δ+ δ- Carbon electrophile: or R X R C A δ+ δ- δ+ abundant OrgChem- Chap20 1

Transcript of Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using...

Page 1: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

1

Page 2: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

How about carbon nucloephile?li it d⇒ limited

Ex) cyanide ion: M+ -CN

acetylide ion:

ylide:

Grignard reagent and organo metallic compound:

OrgChem-Chap20

2

R-X + 2Li → RLi + LiX

Page 3: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

⇒ 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

OrgChem-Chap20

3

Page 4: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

20.1 Enols and Enolate Anions

⇒ both are possible under acidic and basic conditions

In acidic condition

In basic condition

OrgChem-Chap20

4

Page 5: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

5

s

Page 6: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

6

than those of the carbonyl base !

Page 7: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

For

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

For

OrgChem-Chap20

7

Ethoxide can be used (pKa ~ 16)

Page 8: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

8

Page 9: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Under acidic conditions

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

Examples

OrgChem-Chap20

9

Page 10: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Under basic conditions

OrgChem-Chap20

10

Page 11: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Example

OrgChem-Chap20

11

Page 12: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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)

OrgChem-Chap20

12

Page 13: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

⇒ 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

OrgChem-Chap20

13

nucleophilic due to the steric hindrance

Page 14: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

14

Page 15: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

15

Page 16: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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'

OrgChem-Chap20

16

Page 17: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

17

Page 18: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Ch 10 2Ch 10.2

OrgChem-Chap20

18

Page 19: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Ch 10.6

Why?

OrgChem-Chap20

19

Page 20: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

20

Page 21: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Mechanism

OrgChem-Chap20

21

Page 22: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Example

OrgChem-Chap20

22

Page 23: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Diethyl malonate can be used instead of acetic acid

OrgChem-Chap20

23

Page 24: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

24

Page 25: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

Next page

OrgChem-Chap20

25

Page 26: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

26

Page 27: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

27

ester, ketone, and nitrile ⇒ SN2

Page 28: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

<Mechanism>

OrgChem-Chap20

28

Page 29: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

29

Page 30: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

<Examples><Examples>

OrgChem-Chap20

30

Page 31: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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>

OrgChem-Chap20

31

Page 32: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Mixed aldol condensationMixed aldol condensation

4 products =

2 acidic compounds x 2 electrophilic compounds

OrgChem-Chap20

32

Page 33: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

<Example><Example>

OrgChem-Chap20

33

Page 34: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

<Examples>

OrgChem-Chap20

34

Page 35: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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''

OrgChem-Chap20

35

Page 36: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

36

Page 37: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Mechanism of the Claisen Ester Condensation

OrgChem-Chap20

37Step 4 is the reason why this reaction is possible

Page 38: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

38

Page 39: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

39

Page 40: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

<Examples>

OrgChem-Chap20

40

Page 41: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

20.7 Carbon and hydrogen leaving groups

A carbanion as a leaving group

Haloform reaction

Adol condensation

OrgChem-Chap20

41Claisen ester condensation

Page 42: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

A hydride as a leaving group, Cannizzaro reactionCannizzaro reaction

OrgChem-Chap20

42

Page 43: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Cannizzaro reaction

example

OrgChem-Chap20

43

Page 44: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

44

Page 45: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

<Examples>

OrgChem-Chap20

45

Page 46: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

<Examples><Examples>

OrgChem-Chap20

46

Page 47: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

20.9 Other Carbon Nucleophiles

OrgChem-Chap20

47

Page 48: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Example reactionExample reaction

OrgChem-Chap20

48

Page 49: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

E ample reactionExample reaction

OrgChem-Chap20

49

Page 50: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Other Carbon Nucleophiles

OrgChem-Chap20

50

Page 51: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Using two equivalent of LDA

more nucleophic site is reactedmore nucleophic site is reacted

OrgChem-Chap20

51

Page 52: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

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

OrgChem-Chap20

52

Page 53: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

In CH 20 Michael reaction→ enolate and related carbanion

++

α,β-unsaturated carbonyl compound

In Michael reaction only catalytic amount of base is needed

OrgChem-Chap20

53

Page 54: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Michael reaction mechanism

OrgChem-Chap20

54

Page 55: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Examples of Michael reaction

OrgChem-Chap20

55

Page 56: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Robinson annulation⇒ Michael reaction + aldol condensation

OrgChem-Chap20

56

Page 57: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

20.11 Synthesis

Retrosynthetic Arrow

OrgChem-Chap20

57

Page 58: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

58

Page 59: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

59

Page 60: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

60

Page 61: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

61

Page 62: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

Other example

OrgChem-Chap20

62

Page 63: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

SummarySummary

OrgChem-Chap20

63

Page 64: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

64

Page 65: Chapter 20 Enolates / other Carbanions · 2018. 1. 30. · 20.3-4: enolates with alkyl halide using weak or strong bases depending on the ... Ester condensation or Claisen ester condensation

OrgChem-Chap20

65