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Home , Cannizzaro reaction, Enolate

Chapter 20 Enolates / other

C-C bond formation is very important ⇒ larger, more complex organic molecule can be made from smaller ones How? carbon nucleophile + carbon electrophile

⇒ C C C C

O δ+ δ- Carbon electrophile : or RC A RX δ+ ⇒ abundant

OrgChem- 1 Chap20 How about carbon nucloephile? ⇒ limit ed Ex) cyanide ion: M+ -CN

acetylide ion:

ylide:

Grignard reagent and organo metallic compound:

R-X + 2Li → RLi + LiX

OrgChem- 2 Chap20 ⇒ Grignard reagent and organometallic compund are not

useful for SN2 reactions because they are too reactive.

For the SN2 enolates are used Because they are not as reactive as organometallic

compunds, then C-C bond through SN2 can be formed

OrgChem- 3 Chap20 20.1 and Enolate Anions

⇒ both are possible under acidic and basic conditions

In acidic condition

In basic condition

OrgChem- 4 Chap20 Equilibrium constants of carbonyl and tautomers for condition diket High e o r value ne >ke f t or oester

, 1 >

-dicarb 3 dieste o r

nyl co m pound s

OrgChem- 5 Chap20 What kinds of base can we use?

O base O R C CH R C CH R' + BH 2 R' B R''-X

O R C CH R'

Use base whose pKas of conjugate acids are greater than those of the carbonyl base !

OrgChem- 6 Chap20 For

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

For

Ethoxide can be used (pKa ~ 16) OrgChem- 7 Chap20 20.2 Halogenation of the α-Carbon

The reaction of an or with Cl2, Br2, or I 2, under either acid or basic condition

Both acidic and basis conditions can be used

OrgChem- 8 Chap20 Under acidic conditions

The presence of the halogens retards the enolation, so the addition of singggple halogen is possible

Examples

OrgChem- 9 Chap20 Under basic conditions

OrgChem- 10 Chap20 Example

OrgChem- 11 Chap20 20.3 Alkylation of Enolate Anions

⇒ Enolates from , , and nitriles

can be used in S N2 reactions (alkylations). Ex)

OrgChem- 12 Chap20 ⇒ cannot be used in such reactions because they are too reactive (side reactions) 1. Reactions with base O R C H No steric hidrance ! B

2. Reactions with themselves: (later)

LDA: lithium diisopropylamide ⇒ It is a very strong base but not very nucleophilic due to the steric hindrance

OrgChem- 13 Chap20 To avoid the formation of two products, deprotonation of the ketones must produce a single enolate ion. Examples

OrgChem- 14 Chap20 OrgChem- 15 Chap20 20.4 Alkylation of More Stabilized Anions

Strong nucleophiles are normally strong bases, then many side reactions are possible. 1.Elimination 2.Unwanted substitution

O O R-X H3C C CHR' RCCH2 R'

OrgChem- 16 Chap20 Therefore we might need to use less nucleophilic enolates, Then we might need more steps to, still the yield can be higher due to less side reaction. Example Ch 10.2

Ch 10.6

OrgChem- 17 Chap20 Ch 10. 2

OrgChem- 18 Chap20 Ch 10.6

Why?

OrgChem- 19 Chap20 This time, ethyl acetoacetate can be used instead of acetone!

OrgChem- 20 Chap20 Mechanism

OrgChem- 21 Chap20 Example

OrgChem- 22 Chap20 Diethyl malonate can be used instead of acetic acid

OrgChem- 23 Chap20 OrgChem- 24 Chap20 Preparation of substituted β-ketoesters, β-diester, and dinitrile ⇒ without hydrolysis

Next page

OrgChem- 25 Chap20 OrgChem- 26 Chap20 20.5 The Aldol Condensation

((yaldehyde + base ) cannot be used for the alk ylation of alkyl halide, because of the aldol condensation! Carbonyl carbon of aldehyde is much more electrophilic than those of , ketone, and nitrile!

ester, ketone , and nitrile ⇒ SN2

OrgChem- 27 Chap20

OrgChem- 28 Chap20 If the aldol condensation is conducted under very vigorous conditions (higher temperature, longer reaction time, and/or strong base

OrgChem- 29 Chap20

OrgChem- 30 Chap20 KtKetones As less electrophilic, usually no aldol condensation.

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

OrgChem- 31 Chap20 Mixed aldol condensation

4 products = 2 acidic compounds x 2 electrophilic compounds

OrgChem- 32 Chap20 Use aromatic aldehyde ((yonly electro philic ) to get one product. Product is more favorable: conjugation

OrgChem- 33 Chap20

OrgChem- 34 Chap20 20.6 Ester Condensation

20.3-4: enolates with alkyl halide using weak or strong bases depending on the acidity.

O base O RCCH RCCH R' + BH 2 R' B R''-X

O RCCH R' R''

OrgChem- 35 Chap20 20.5: enolate with aldehyde using weaker bases. ⇒ Aldol condensation

20. 6: enolate with ester using weaker bases. ⇒ Ester condensation or Claisen ester condensation

OrgChem- 36 Chap20 Mechanism of the Claisen Ester Condensation

Step 4 is the reason why this reaction is possible OrgChem- 37 Chap20 For the compounds with only one on the α-carbon, Step 4 is impossible.

Then th e est er cond ensati on i s i mpossibl e

If stronger base is used, then condensation is possible

OrgChem- 38 Chap20 Dieckmann condensatoin ⇒ Intramolecular ester condensation

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

OrgChem- 39 Chap20

OrgChem- 40 Chap20 20.7 Carbon and hydrogen leaving groups

A as a

Haloform reaction

Adol condensation

Claisen ester condensation OrgChem- 41 Chap20 A hydride as a leaving group, Cannizzaro reaction

OrgChem- 42 Chap20 Cannizzaro reaction

example

OrgChem- 43 Chap20 20.8 Enamines

The enamine can be used as a carbon nucleophile !

In ch 18.8

OrgChem- 44 Chap20 α-carbon is nucleophilic, still weaker nucleophile than

the enolates. Therefore for SN2 reaction, the alkyl halide must be very reactive such as:

OrgChem- 45 Chap20

OrgChem- 46 Chap20 20.9 Other Carbon Nucleophiles

OrgChem- 47 Chap20 Example reaction

OrgChem- 48 Chap20 Ex ample reaction

OrgChem- 49 Chap20 Other Carbon Nucleophiles

OrgChem- 50 Chap20 Using two equivalent of LDA more nucleophic site is reacted

OrgChem- 51 Chap20 20.10 Conjugated Addition

O 1,2 addition: Grignard reagent, hydride C → stronger nucleophile CH2

1,4 addition: cyanide, amine 1,2 addition → ltilhilless reactive nucleophile or sterically hindered 1,4 addition See CH 18.10

OrgChem- 52 Chap20 In CH 20 → enolate and related carbanion + α,β-unsaturated carbonyl compound

In Michael reaction only catalytic amount of base is needed

OrgChem- 53 Chap20 Michael reaction mechanism

OrgChem- 54 Chap20 Examples of Michael reaction

OrgChem- 55 Chap20 Robinson annulation ⇒ Michael reaction + aldol condensation

OrgChem- 56 Chap20 20.11 Synthesis

Retrosynthetic Arrow

OrgChem- 57 Chap20 OrgChem- 58 Chap20 OrgChem- 59 Chap20 OrgChem- 60 Chap20 OrgChem- 61 Chap20 Other example

OrgChem- 62 Chap20 Summary

OrgChem- 63 Chap20 OrgChem- 64 Chap20 OrgChem- 65 Chap20